lactoferrin and Inflammation

Milk-derived bioactive proteins have increasingly gained attention and consideration throughout the world due to their high-quality amino acids and multiple health-promoting attributes. Apparently, being at the forefront of functional foods, these bioactive proteins are also suggested as potential alternatives for the management of various complex diseases. In this review, we will focus on lactoferrin (LF) and osteopontin (OPN), two multifunctional dairy proteins, as well as to their naturally occurring bioactive LF-OPN complex. While describing their wide variety of physiological, biochemical, and nutritional functionalities, we will emphasize their specific roles in the perinatal period. Afterwards, we will evaluate their ability to control oxidative stress, inflammation, gut mucosal barrier, and intestinal microbiota in link with cardiometabolic disorders (CMD) (obesity, insulin resistance, dyslipidemia, and hypertension) and associated complications (diabetes and atherosclerosis). This review will not only attempt to highlight the mechanisms of action, but it will critically discuss the potential therapeutic applications of the underlined bioactive proteins in CMD.

Topics: Cardiovascular Diseases; Female; Humans; Inflammation; Lactoferrin; Milk Proteins; Obesity; Osteopontin; Pregnancy

Lactoferrin is a versatile protein with important modulatory functions in inflammation and immune response. This glycoprotein can bind and sequester iron and LPS, thereby intervening in certain signaling pathways and biological processes. In the present meta-analysis, we aimed to pool experimental data regarding the immunomodulatory effects of lactoferrin and its derived peptides on the NF-κB signaling pathway.. We searched PubMed, Google Scholar, and Web of Science databases and obtained all related articles published before April 2022. Finally, 25 eligible studies were selected, and their reports were analyzed.. We used Review Manager Version 5.2 to compute the standardized mean difference (SMD) and its 95% confidence interval. In addition, the source of heterogeneity was explored using meta-regression and sensitivity analysis. The symmetry of the funnel plot and Egger's test were also used to evaluate publication bias utilizing Comprehensive Meta-Analysis Version 2.. Comparing the group of cells and animals exposed to lipopolysaccharide alone with the group that received pretreatment with lactoferrin and its derivatives, we observed significant reductions in TNF-α, IL-1 beta, and IL-6 levels by 8.73 pg/mL, 2.21 pg/mL, and 3.24 pg/mL, respectively, in the second group. Additionally, IKK-β, p-IκB, and NF-κB (p65) levels were significantly lower by 7.37-fold, 15.02-fold, and 3.88-fold, respectively, in various cells and tissues.. Based on the results of this meta-analysis, lactoferrin and its derived peptides can be considered potent prophylactic and therapeutic candidates against inflammation-associated diseases by targeting the NF-kB pathway.

Topics: Animals; Immunity; Inflammation; Lactoferrin; Lipopolysaccharides; NF-kappa B; Peptides; Signal Transduction

Many pathological conditions, including obesity, diabetes, hypertension, heart disease, and cancer, are associated with abnormal metabolic states. The progressive loss of metabolic control is commonly characterized by insulin resistance, atherogenic dyslipidemia, inflammation, central obesity, and hypertension, a cluster of metabolic dysregulations usually referred to as the "metabolic syndrome". Recently, nutraceuticals have gained attention for the generalized perception that natural substances may be synonymous with health and balance, thus becoming favorable candidates for the adjuvant treatment of metabolic dysregulations. Among nutraceutical proteins, lactoferrin (Lf), an iron-binding glycoprotein of the innate immune system, has been widely recognized for its multifaceted activities and high tolerance. As this review shows, Lf can exert a dual role in human metabolism, either boosting or resetting it under physiological and pathological conditions, respectively. Lf consumption is safe and is associated with several benefits for human health, including the promotion of oral and gastrointestinal homeostasis, control of glucose and lipid metabolism, reduction of systemic inflammation, and regulation of iron absorption and balance. Overall, Lf can be recommended as a promising natural, completely non-toxic adjuvant for application as a long-term prophylaxis in the therapy for metabolic disorders, such as insulin resistance/type II diabetes and the metabolic syndrome.

Topics: Adjuvants, Immunologic; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypertension; Inflammation; Insulin Resistance; Iron; Lactoferrin; Metabolic Syndrome; Obesity

Lactoferrin (Lf) is a glycoprotein present in human and bovine milk with antimicrobial and immune-modulating properties. This review aimed to examine the evidence for the effect of Lf supplementation on inflammation, immune function, and respiratory tract infections (RTIs) in humans. Online databases were searched up to December 2020 to identify relevant, English-language articles that examined the effect of Lf supplementation in human subjects of all ages, on either inflammation, immune cell populations or activity, or the incidence, duration, or severity of respiratory illness or RTIs. Twenty-five studies (n = 20 studies in adults) were included, of which 8 of 13 studies (61%) in adults reported a decrease in at least 1 systemic inflammatory biomarker. Immune function improved in 6 of 8 studies (75%) in adults, with changes in immune cell populations in 2 of 6 studies (33%), and changes in immune cell activity in 2 of 5 studies (40%). RTI outcomes were reduced in 6 of 10 studies (60%) (n = 5 in adults, n = 5 in children), with decreased incidence in 3 of 9 studies (33%), and either decreased frequency (2/4, 50%) or duration (3/6, 50%) in 50% of studies. In adults, Lf reduced IL-6 [mean difference (MD): -24.9 pg/mL; 95% CI: -41.64, -8.08 pg/mL], but not C-reactive protein (CRP) [standardized mean difference: -0.09; 95% CI: -0.82, 0.65], or NK cell cytotoxicity [MD: 4.84%; 95% CI: -3.93, 13.60%]. RTI incidence was reduced in infants and children (OR: 0.78; 95% CI: 0.61, 0.98) but not in adults (OR: 1.00; 95% CI: 0.76, 1.32). Clinical studies on Lf supplementation are limited, although findings show 200 mg Lf/d reduces systemic inflammation, while formulas containing 35-833 mg Lf/d may reduce RTI incidence in infants and children, suggesting improved immune function. Future research is required to determine optimal supplementation strategies and populations most likely to benefit from Lf supplementation. This trial was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232186) as CRD42021232186.

Topics: Adult; Biomarkers; Child; Dietary Supplements; Glycoproteins; Humans; Immunity; Infant; Inflammation; Interleukin-6; Lactoferrin; Respiratory Tract Infections

The oral cavity is a non-uniform, extraordinary environment characterized by mucosal, epithelial, abiotic surfaces and secretions as saliva. Aerobic and anaerobic commensal and pathogenic microorganisms colonize the tongue, teeth, jowl, gingiva, and periodontium. Commensals exert an important role in host defenses, while pathogenic microorganisms can nullify this protective function causing oral and systemic diseases. Every day, 750-1000 mL of saliva, containing several host defense constituents including lactoferrin (Lf), are secreted and swallowed. Lf is a multifunctional iron-chelating cationic glycoprotein of innate immunity. Depending on, or regardless of its iron-binding ability, Lf exerts bacteriostatic, bactericidal, antibiofilm, antioxidant, antiadhesive, anti-invasive, and anti-inflammatory activities. Here, we report the protective role of Lf in different oral pathologies, such as xerostomia, halitosis, alveolar or maxillary bone damage, gingivitis, periodontitis, and black stain. Unlike antibiotic therapy, which is ineffective against bacteria that are within a biofilm, adherent, or intracellular, the topical administration of Lf, through its simultaneous activity against microbial replication, biofilms, adhesion, and invasiveness, as well as inflammation, has been proven to be efficient in the treatment of all known oral pathologies without any adverse effects.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Bacteria; Biofilms; Humans; Inflammation; Lactoferrin; Mouth

Recently, the world has been dealing with a devastating global pandemic coronavirus infection, with more than 12 million infected worldwide and over 300,000 deaths as of May 15th 2020, related to a novel coronavirus (2019-nCoV), characterized by a spherical morphology and identified through next-generation sequencing. Although the respiratory tract is the primary portal of entry of SARS-CoV-2, gastrointestinal involvement associated with nausea, vomiting and diarrhoea may also occur. No drug or vaccine has been approved due to the absence of evidence deriving from rigorous clinical trials. Increasing interest has been highlighted on the possible preventative role and adjunct treatment of lactoferrin, glycoprotein of human secretions part of a non-specific defensive system, known to play a crucial role against microbial and viral infections and exerting anti-inflammatory effects on different mucosal surfaces and able to regulate iron metabolism. In this review, analysing lactoferrin properties, we propose designing a clinical trial to evaluate and verify its effect using a dual combination treatment with local, solubilized intranasal spray formulation and oral administration. Lactoferrin could counteract the coronavirus infection and inflammation, acting either as natural barrier of both respiratory and intestinal mucosa or reverting the iron disorders related to the viral colonization.

Topics: Angiotensin-Converting Enzyme 2; Betacoronavirus; Coronavirus Infections; COVID-19; Humans; Inflammation; Intestinal Mucosa; Iron; Lactoferrin; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Respiratory Mucosa; SARS-CoV-2; Virus Internalization

Irritable bowel syndrome (IBS) is among the most commonly encountered conditions in primary care and gastroenterology. There is ample evidence that an IBS diagnosis based on symptom-based criteria and exclusion of alarm features that would otherwise support diagnostic testing is accurate and durable. For many clinicians, however, IBS remains a diagnosis of exclusion because of concern surrounding missed diagnoses of inflammatory bowel disease (IBD) or other organic gastrointestinal diseases. Using blood and/or fecal biomarker tests to shift the precolonoscopy probability of IBD in patients with symptoms mimicking IBS is becoming an increasingly reasonable practice with improvement in 'preliminary' tests.. Fecal calprotectin (FCP) testing appears to be the most sensitive preliminary test for discriminating IBD from IBS. Although both fecal lactoferrin and FCP were superior to serum C-reactive peptide (CRP) in their diagnostic accuracy, FCP is superior to fecal lactoferrin based on available literature.. In patients with IBS with diarrhea who have not undergone previous extensive evaluation, the ability of screening tests to detect colonic inflammation is improving. FCP and fecal lactoferrin are reliable predictors of colonic inflammation and should be considered for standard testing in patients with IBS-D symptoms to help identify those who would benefit most from colonoscopy. Although predictive, there currently are no fecal or serum tests that can definitively identify or subtype IBD.

Topics: Biomarkers; C-Reactive Protein; Diagnosis, Differential; Endoscopy, Gastrointestinal; Feces; Humans; Inflammation; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Lactoferrin; Leukocyte L1 Antigen Complex; Reproducibility of Results

The review presents the pathobiochemical and molecular mechanisms of sputum formation in patients with cystic fibrosis associated with the pathophysiological features of the disease. Statistical data on the prevalence of this pathology in the world and in the Russian Federation are presented. The mechanisms of sputum formation and disorders of the mucociliary apparatus, leading to the accumulation of viscous bronchopulmonary secret in cystic fibrosis, are considered. The principles of the relationship between the rheological properties of sputum and the formation of inflammation in the lungs with the addition of a concomitant specific microflora in the bronchopulmonary system in patients with cystic fibrosis are presented. Describes the opportunities for biochemical studies of sputum of patients with this pathology: determining the activity of enzymes (myeloperoxidase), the content of proteinase inhibitors (α2-macroglobulin and α1-antitrypsin) and proinflammatory cytokines (IL-8 and TNFa), concentrations of iron and ferriferous proteins (lactoferrin and ferritin), which makes biochemical studies of sputum available, non-invasive, quick and cost-effective method of diagnosis, which can be widely used as an auxiliary laboratory method and makes it possible to use these metabolites as diagnostic markers to assess the severity of inflammation and infection of the lower respiratory tract and predict the development of respiratory complications in patients with cystic fibrosis.

Topics: Cystic Fibrosis; Cytokines; Ferritins; Humans; Inflammation; Lactoferrin; Peroxidase; Protease Inhibitors; Sputum

Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer's disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in

Topics: Anemia; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Biomarkers; Humans; Inflammation; Iron; Lactoferrin; Sepsis

Inflammation is the result of the loss of host's resilience towards the surrounding world. At gross tissue level, inflammation coincides with fluid leakage from vessels, swelling, and blood stasis and extravasation of mononuclear/macrophage cells. Biochemically, these events lead to anoxia and dramatic changes: interruption of the mitochondrial oxidative phosphorylation, influx of the M1 macrophage subset, which live on anaerobic glycolysis. Fall of ATP then leads to energy shortage and debt. In their chronic forms, these phenomena are now known to mark a number of degenerative disorders that have invaded the Western World since the last century: Parkinson's disease, Alzheimer's syndromes, rheumatic diseases, metabolic diseases. Intriguingly, these affections seem to derive from the gut, along two possible pathways. A sort of ascending loss of function caused by accumulation of (and hyperreactivity to) proteins released to restrain spread of enteric viruses: the alpha-synucleins, now increasingly spotted in relation to Parkinson's pathogenesis. The second pathway would entail the intellectual decline perhaps brought about by large use of food containing the proteins of red processed meat. The bacterium Bilophila wadsworthia, thriving in this meat, can erode the mucus layer on colon surfaces, allowing further bacterial flora to approach lining cells, so upgrading the alarm state. We discuss two strategies to prevent such instability from ending up to full-blown inflammatory bowel disease: physical exercise and systematic switch to fibre-containing diets.

Topics: Animals; Biomarkers; Disease Susceptibility; Humans; Hypoxia; Inflammation; Iron; Lactoferrin; Microbiota; Oxidative Stress; Signal Transduction

Context • Diet-induced, metabolic endotoxemia is emerging as an important contributory factor to the development of a wide range of chronic diseases, including cardiometabolic, autoimmune, psychiatric, and neurodegenerative illnesses. Emerging human clinical studies have demonstrated that diet and dietary components are potent modifiers of circulating endotoxins and can be used to reduce plasma levels significantly and improve metabolic health. Objective • The aim of the current study was to explore briefly the concept of metabolic endotoxemia and its relationship to disease development, to examine the influence of diet and dietary components on circulating endotoxins, and, finally, discuss the clinical relevance of nutritional interventions for management of metabolic endotoxemia. Design • The researcher performed a literature review of dietary and nutritional interactions with metabolic endotoxemia with a focus on studies relevant to clinical practice. Setting • The study took place at the UK College of Nutrition and Health (London, England). Results • Improving dietary quality, optimizing the intake of phytonutrient-rich foods, improving micronutrient status, consuming fermented foods, manipulating the gut microflora with prebiotics and probiotics, and using specific nutritional supplements, such as glutamine, lactoferrin, resveratrol, and berberine, have been shown to be effective in targeting metabolic endotoxemia. Conclusions • Diet, dietary components, and nutritional supplements, including prebiotics and probiotics, have demonstrated the ability to provide clinically important reductions in circulating endotoxins and improve related sequels, such as inflammation and other negative health markers. The development of personalized nutritional interventions for the management of metabolic endotoxemia is a promising area for future research due to the potential of such interventions to improve multiple aspects of human health and mitigate a wide range of chronic diseases.

Topics: Anti-Infective Agents; Berberine; Diet Therapy; Dysbiosis; Endotoxemia; Fermentation; Glutamine; Humans; Inflammation; Intestinal Mucosa; Lactoferrin; Metabolic Diseases; Permeability; Polyphenols; Prebiotics; Probiotics; Vitamins

Human lactoferrin (hLf), an iron-binding multifunctional cationic glycoprotein secreted by exocrine glands and by neutrophils, is a key element of host defenses. HLf and bovine Lf (bLf), possessing high sequence homology and identical functions, inhibit bacterial growth and biofilm dependently from iron binding ability while, independently, bacterial adhesion to and the entry into cells. In infected/inflamed host cells, bLf exerts an anti-inflammatory activity against interleukin-6 (IL-6), thus up-regulating ferroportin (Fpn) and transferrin receptor 1 (TfR1) and down-regulating ferritin (Ftn), pivotal actors of iron and inflammatory homeostasis (IIH). Consequently, bLf inhibits intracellular iron overload, an unsafe condition enhancing in vivo susceptibility to infections, as well as anemia of inflammation (AI), re-establishing IIH. In pregnant women, affected by AI, bLf oral administration decreases IL-6 and increases hematological parameters. This surprising effect is unrelated to iron supplementation by bLf (80 μg instead of 1-2 mg/day), but to its role on IIH. AI is unrelated to the lack of iron, but to iron delocalization: cellular/tissue overload and blood deficiency. BLf cures AI by restoring iron from cells to blood through Fpn up-expression. Indeed, anti-inflammatory activity of oral and intravaginal bLf prevents preterm delivery. Promising bLf treatments can prevent/cure transitory inflammation/anemia/oral pathologies in athletes.

Topics: Anemia; Anemia, Iron-Deficiency; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Female; Glycoproteins; Homeostasis; Humans; Inflammation; Iron; Lactoferrin; Oral Health; Pregnancy; Premature Birth; Protein Binding; Structure-Activity Relationship

Obesity is a strong predictive factor in the development of chronic disease and has now superseded undernutrition as a major public health issue. Chronic inflammation is one mechanism thought to link excess body weight with disease. Increasingly, the gut and its extensive population of commensal microflora are recognized as playing an important role in the development of obesity-related chronic inflammation. Obesity and a high fat diet are associated with altered commensal microbial communities and increased intestinal permeability which contributes to systemic inflammation as a result of the translocation of lipopolysaccharide into the circulation and metabolic endotoxemia. Various milk proteins are showing promise in the prevention and treatment of obesity and chronic low-grade inflammation via reductions in visceral fat, neutralization of bacteria at the mucosa and reduced intestinal permeability. In this review, we focus on evidence supporting the potential antiobesogenic and anti-inflammatory effects of bovine whey-derived lactoferrin and immunoglobulins.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Body Weight; Cattle; Chronic Disease; Disease Models, Animal; Endotoxemia; Functional Food; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Immunoglobulins; Inflammation; Lactoferrin; Lipopolysaccharides; Obesity; Randomized Controlled Trials as Topic; Whey

Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (>4 weeks in duration) are more elusive. We review the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extraepithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in the assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.

Topics: C-Reactive Protein; Chromogranins; Chronic Disease; Diarrhea; Feces; Gastrointestinal Motility; Humans; Inflammation; Intestinal Absorption; Intestinal Mucosa; Intestinal Secretions; Intestines; Irritable Bowel Syndrome; Lactoferrin; Leukocyte L1 Antigen Complex; Osmolar Concentration; Permeability; Prostaglandins; Serotonin; Substance P

Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly cationic charge. Noteworthy, Lf also exhibits immunomodulatory activities performing up- and down-regulation of innate and adaptive immune cells, contributing to the homeostasis in mucosal surfaces exposed to myriad of microbial agents, such as the gastrointestinal and respiratory tracts. Although the inflammatory process is essential for the control of invasive infectious agents, the development of an exacerbated or chronic inflammation results in tissue damage with life-threatening consequences. In this review, we highlight recent findings in in vitro and in vivo models of the gut, lung, oral cavity, mammary gland, and liver infections that provide experimental evidence supporting the therapeutic role of human and bovine Lf in promoting some parameters of inflammation and protecting against the deleterious effects of bacterial, viral, fungal and protozoan-associated inflammation. Thus, this new knowledge of Lf immunomodulation paves the way to more effective design of treatments that include native or synthetic Lf derivatives, which may be useful to reduce immune-mediated tissue damage in infectious diseases.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Communicable Diseases; Humans; Immunity, Innate; Immunologic Factors; Immunomodulation; Inflammation; Lactoferrin

Lactoferrin is thought to be the most polyvalent protein present in host defense against tissue injuries and infections in vertebrates. Owing to the propensity of its basic N-terminal domain to interact with various microbial and host targets, lactoferrin not only has antimicrobial properties, but also modulates the innate and adaptive immune responses. Lactoferrin may indeed up- and downregulate immune cell activation, migration, and growth. Whereas the immunomodulatory properties of lactoferrin are evidenced from in vivo studies using either lactoferrin-knockout, lactoferrin-overexpressing transgenic models, and dietary lactoferrin, few mechanisms from in vitro studies have been proposed to explain these properties. The best characterized lactoferrin targets are negatively charged molecules. They encompass pro-inflammatory microbial molecules, such as pathogen-associated molecular patterns (eg, lipopolysaccharide), but also host components such as DNA, the glycosaminoglycan chains of proteoglycans, and surface cell receptors. Signaling through these receptors is thought to be the main lever used by lactoferrin to influence immune cells and cytokine-balance-controlling cell activity. This article aims to review our current understanding, though incomplete, of the many ways lactoferrin influences the complex immune machinery and the known and putative mechanisms that may explain its properties.

Topics: Adaptive Immunity; Cytokines; Humans; Immunity, Innate; Inflammation; Lactoferrin; Signal Transduction

Lactoferrin (Lf), an iron-binding protein from the transferrin family has been reported to have numerous functions. Even though Lf was first isolated from milk, it is also found in most exocrine secretions and in the secondary granules of neutrophils. Antimicrobial and anti-inflammatory activity reports on lactoferrin identified its significance in host defense against infection and extreme inflammation. Anticarcinogenic reports on lactoferrin make this protein even more valuable. This review is focused on the structural configuration of iron-containing and iron-free forms of lactoferrin obtained from different sources such as goat, camel and bovine. Apart for emphasizing on the specific beneficial properties of lactoferrin from each of these sources, the general antimicrobial, immunomodulatory and anticancer activities of lactoferrin are discussed here. Implementation of nanomedicinial strategies that enhance the bioactive function of lactoferrin are also discussed, along with information on lactoferrin in clinical trials.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Camelus; Cattle; Clinical Trials as Topic; Goats; Humans; Immunity, Innate; Inflammation; Iron; Iron Chelating Agents; Lactoferrin; Neoplasms; Neutrophils

In the recent decades the rapid development of the studies on new methods used in diagnosis, differential diagnosis, and monitoring the treatment of inflammatory bowel diseases has been observed. To the diagnostics of gastrointestinal disorders new methods such as endoscopic capsule and imaging methods including magnetic resonance have been introduced. Markers of inflammation detected in stool play significant role in the diagnostics. To the best known belong calprotectine and lactoferrin, which are produced by neutral granulocytes. In the present review we have presented the clinical usefulness of detection in the stool of calprotectin, lectoferrin, S100A12 protein and pyruvate kinase. Clinical usefulness of these markers were used in diagnosis, assessment of the treatment results, disease relapse and mucosal healing in inflammatory bowel disease. Determination of fecal calprotectin and lactoferrin in the process of mucosal healing in ulcerative colitis or Crohn's disease are of particular value. Confirmation of these results in multicenter prospective trials will enable in the future to reduce the number of control colonoscopies, which in children are performer under general anesthesia.

Topics: Adolescent; Biomarkers; Capsule Endoscopy; Child; Child, Preschool; Colonoscopy; Diagnostic Imaging; Feces; Humans; Inflammation; Inflammatory Bowel Diseases; Lactoferrin; Leukocyte L1 Antigen Complex; Monitoring, Physiologic; Pyruvate Kinase; S100A12 Protein; Treatment Outcome

There is an intense interest among neonatal caregivers as to whether lactoferrin given enterally may reduce the incidence of necrotizing enterocolitis in preterm infants. This review presents scientific and clinical evidence that lactoferrin alleviates or prevents this life-threatening disease.. Preclinical studies in neonatal rats showed that lactoferrin given orally before enteral infection with pathogenic Escherichia coli reduced bacteremia and mortality. A multicentered clinical trial found that very low-birth weight preterm infants given bovine lactoferrin had a significant reduction in late-onset sepsis; there was also a trend towards a diminished incidence of necrotizing enterocolitis. Although multicentered trials of lactoferrin use in preterm infants are near completion, regulatory burdens required to bring lactoferrin to the bedside may limit its availability.. Extremely preterm infants should receive colostrum, a natural lactoferrin concentrate, immediately after birth and, ideally, continue on breast milk throughout the hospital stay. This practice appears well tolerated, but additional experience will tell us whether this practice reduces the prevalence of necrotizing enterocolitis.

Topics: Animals; Colostrum; Enteral Nutrition; Enterocolitis, Necrotizing; Gastrointestinal Tract; Humans; Immunity, Innate; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Inflammation; Lactoferrin; Randomized Controlled Trials as Topic; Sepsis

Currently, obesity-associated metabolic disturbances are envisioned as chronic inflammatory processes, characterized by activation of both innate and adaptive immunity. Although the features of chronic inflammation in obese subjects are clearly defined, the signals and mechanisms that trigger chronic inflammation are not well understood. Recent studies suggest an imbalance in circulating antimicrobial proteins as a possible cause of obesity-associated metabolic disturbances and insulin resistance. This imbalance promotes a relative failure in the capacity of buffering external insults and might cause the onset of chronic inflammation and immunologic alterations in obesity. Here, we review the current literature on the possible role of circulating antimicrobial proteins in obesity-associated immunologic alterations.

Topics: Antimicrobial Cationic Peptides; Humans; Immune System Diseases; Inflammation; Lactoferrin; Lipocalins; Obesity

Acute and chronic inflammation commonly occurs throughout the oral cavity. The most common causes are physical damage and microbial infections, and less frequently immune reactions and malignant changes. All of these processes result in the induction of antimicrobial peptides, chemokines and cytokines that lead to cellular infiltrates, a vascular response, tissue destruction and cellular proliferation. A fascinating concept developing in the current literature suggests that antimicrobial peptides modulate the production of chemokines, cytokines and other cellular mediators and that this may have a larger ramification as an underlying mechanism mediating inflammation. Here, we propose that the ability of antimicrobial peptides to induce chemokines and anti-inflammatory or proinflammatory cytokines plays an important role in the early events of oral inflammation and may be a target for the prevention or treatment of oral inflammatory conditions.

Topics: Anti-Inflammatory Agents; Antimicrobial Cationic Peptides; Bacterial Infections; Cytokines; Humans; Immunity, Innate; Immunomodulation; Inflammation; Lactoferrin; Lipopolysaccharides; Mouth; Protein Binding; Saliva

Bovine lactoferricin (LfcinB) is a multifunctional peptide derived from bovine lactoferrin that demonstrates antibacterial, antifungal, antiviral, antitumor, and immunomodulatory activities. Recently, studies have focused on the anti-catabolic and anti-inflammatory potential of LfcinB. LfcinB is able to modulate the effects cytokines such as IL-1 and fibroblast growth factor 2 as well as promote specific cartilage anabolic factors. These properties are particularly important in maintaining cartilage homeostasis and preventing a catabolic state, which leads to clinical pathology. This review focuses on the recent literature elucidating the role of LfcinB in preventing cartilage degradation.

Topics: Animals; Anti-Inflammatory Agents; Cartilage; Endopeptidases; Fibroblast Growth Factor 2; Inflammation; Interleukin-1; Intervertebral Disc; Lactoferrin; Matrix Metalloproteinases

Lactoferrin (Lf), a multifunctional protein of the innate immune response, seems to act as a permeabilizing agent of Gram negative bacteria, apparently due to its interaction with enterobacterial lipopolysaccharide (LPS) on the bacterial surface. In both human and bovine Lf, a six residue sequence lying in an 18-loop region of the lactoferricin domain is key to Lf-LPS binding. There is much evidence that, by its action on LPS, Lf destabilizes the bacterial membrane and therefore increases bacterial permeability. By itself, Lf is not an effective antibacterial agent, but it permits the penetration of the bacterial membrane by some antibacterial substances whose hydrophobicity otherwise limits their efficacy. Additionally, Lf neutralizes free LPS by keeping the latter from forming complexes that activate TLR-4 signaling pathways. Such pathways, when over-activated, lead to the abundant production of pro-inflammatory mediators such as tumor necrosis factor (TNF) with fatal consequences to the host. The effect of Lf in reducing inflammation and destabilizing Gram negative bacteria has clinical implications in the control of sepsis, multiple organ dysfunction and bacterial invasion.

Topics: Animals; Anti-Bacterial Agents; Gram-Negative Bacteria; Humans; Inflammation; Lactoferrin; Lipopolysaccharides; Myelopoiesis

Several attempts have been made in the last two decades to investigate ulcerative colitis (UC) patients during the natural course of the disease so as to identify appropriate surrogate markers of disease activity. Most patients with quiescent inflammatory bowel disease have low grade inflammation and it is possible that relapse occurs only once the inflammatory process crosses a critical intensity. Since inflammation is a continuous process, its direct assessment may provide us a quantitative pre-symptomatic measure of imminent relapse. If substantial, it may allow targeted treatment early, to avert relapse or formulate newer therapeutic strategies to maintain symptomatic remission. It is clinically very important to identify these patients at a subclinical stage, noninvasively, by various biomarkers. Biomarkers help to gain an objective measurement of disease activity as symptoms are often subjective. Biomarkers also help to avoid invasive procedures which are often a burden to the patient and the health care system. If an ideal biomarker existed for UC, it would greatly facilitate the work of the gastroenterologist treating these patients. Both "classical" and "emerging" biomarkers of relevance for UC have been studied, but the quest for an ideal biomarker still continues. In this brief review we describe various biomarkers of clinical importance.

Topics: Biomarkers; C-Reactive Protein; Colitis, Ulcerative; Feces; Humans; Inflammation; Lactoferrin; Leukocyte L1 Antigen Complex; Peroxidase; Severity of Illness Index

Until relatively recently, the only significant source of lactoferrin in the diet was human lactoferrin, provided in breast milk. Today, however, bovine lactoferrin, isolated by dairy technology, as well as recombinant human lactoferrin are commercially available and can be added to foods and clinical products with perceived benefits to the consumer. In this review, the potential biological functions of dietary lactoferrin are described and critically examined.. Ingested lactoferrin has been suggested to exert antibacterial and antiviral activities in the intestine, in part through a direct effect on pathogens, but possibly also affecting mucosal immune function. The latter function is most likely mediated by lactoferrin being taken up by cells via a unique receptor-mediated pathway and affecting gene transcription. Lactoferrin has also been shown to enhance iron status of infants and pregnant women, possibly also via the receptor-mediated pathway. In addition, lactoferrin can stimulate intestinal cell proliferation and differentiation, causing expansion of tissue mass and absorptive capacity. On the contrary, lactoferrin has been shown to inhibit carcinogenesis. Recent findings also suggest that oral lactoferrin treatment may have an anti-inflammatory effect on pregnant women, reducing pregnancy complications.. Lactoferrin treatment may have beneficial preventive and therapeutic effects on infection, inflammation, and cancer as well as enhancing iron status and growth in vulnerable groups.

Topics: Anemia, Iron-Deficiency; Animals; Dietary Supplements; Female; Humans; Infant; Infections; Inflammation; Iron; Lactoferrin; Neoplasms; Pregnancy; Pregnancy Complications

Lactoferrin (Lf) is an iron-binding glycoprotein of the transferrin family that is expressed and secreted by glandular cells and found in the secondary granules of neutrophils from which it is released in infected tissues and blood during the inflammatory process. Initially described as an iron-binding molecule with bacteriostatic properties, Lf is now known to be a multifunctional or multi-tasking protein. It is a major component of the innate immune system of mammals. Its protective effects range from direct anti-microbial activities against a large panel of microorganisms including bacteria, viruses, fungi, and parasites, to anti-inflammatory and anti-cancer activities. While iron chelation is central to some of the biological functions of Lf, other activities involve interactions of Lf with molecular and cellular components of both hosts and pathogens. Its powerful antimicrobial activities, immunomodulatory properties and prevention of septic shock, anti-carcinogenic functions and its growing importance in iron delivery and bone growth, combined with the data obtained either by in vivo studies or clinical trials, make this molecule and its derivatives very promising tools for health or nutritional applications.

Topics: Animals; Apoptosis; Blood Bactericidal Activity; Bone Remodeling; Cattle; Humans; Immunity, Innate; Infections; Inflammation; Intestinal Absorption; Iron, Dietary; Lactoferrin; Mammals; Models, Molecular; Neoplasms; Neovascularization, Physiologic; Protein Conformation

Despite the use of potent antimicrobials, neonatal sepsis and necrotizing enterocolitis are associated with significant mortality and morbidity. The emergence of microbial antibiotic resistance is a grave concern. Inflammation secondary to sepsis and necrotizing enterocolitis increases pulmonary and cerebral morbidity. New strategies that target inflammation and reduce the emergence of antibiotic resistance are urgently needed. Lactoferrin has broad-spectrum antimicrobial and immunomodulatory activities. In animal models of colitis, lactoferrin reduces inflammatory injury. Lactoferrin also induces the receptor-mediated proliferation and differentiation of intestinal cells. A randomized, controlled trial of lactoferrin in premature neonates to prevent late-onset sepsis is currently in progress. Lactoferrin is a promising agent in the prevention of neonatal sepsis and necrotizing enterocolitis but needs further evaluation to confirm its safety, tolerability and efficacy.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Enterocolitis, Necrotizing; Humans; Immunologic Factors; Infant, Newborn; Infant, Premature; Inflammation; Lactoferrin; Sepsis

Human lactoferrin is a natural defense protein belonging to the innate immune system present in several body fluids and secretions, as well as in the secondary granules of polymorphonuclear neutrophils. Lactoferrin and its derivatives have pleiotropic functions including broad-spectrum anti-microbial activity, anti-tumor activity, regulation of cell growth and differentiation, and modulation of inflammatory as well as humoral and cellular immune responses. This is the reason why much research has addressed the potential therapeutic activity of these molecules in different clinical settings, especially regarding infectious diseases and uncontrolled inflammatory conditions. In patients with hematological malignancies treated with a hematopoietic stem cell transplantation (HSCT), morbidity and mortality due to infections and uncontrolled inflammation remains high, despite many advances in supportive care. These life-threatening complications are a result of the damage caused by the conditioning regimens to the mucosal barrier, and the innate and adaptive, humoral, and cellular immune defenses. These complications necessitate the continued exploration of new treatment modalities. Systemic and probably local levels of lactoferrin are decreased following HSCT. Therefore, the use of lactoferrin, or short peptide derivatives that retain the cationic N-terminal moiety that is essential for the anti-microbial and anti-inflammatory activity, may prove to be a promising versatile class of agents for managing the complications that arise from HSCT.

Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infections; Inflammation; Lactoferrin; Postoperative Complications; Transplantation Immunology

Lactoferrin, an iron-binding glycoprotein, can be regarded as a cell-secreted mediator that bridges innate and adaptive immune function by regulating target cell response. It is a major pleiotropic mediator that directly assists in the development of T-helper cell polarization. The aim of this minireview is to provide a summary of the most recent work presented at the Lactoferrin Minisymposium at the University of Texas, Health Science Center at Houston, Texas, USA, regarding role of lactoferrin in maintaining immune homeostasis. The data presented here lay emphasis on the significance of lactoferrin in the resolution or progression of the immune responses, thus giving lactoferrin bookend properties in controlling the initial reactions to infectious assault, trauma, and injury. These findings may be critically important in the development of therapeutically relevant protocols.

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Cytokines; Endotoxemia; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Inflammation; Intestinal Mucosa; Iron; Lactoferrin; Reactive Oxygen Species

During acute inflammation, immune homeostasis is lost leading to destructive immunopathology. Homeostasis is normally dependent upon coordinated interactions among the various lymphoid, phagocytic and somatic cells that comprise the immune system. In general, these interactions are tightly regulated to obtain a balance between mechanisms necessary to eliminate harmful pathogens, and overaggressive responses leading to destruction of host tissue. Activation of immunoeffector cells results in pro-inflammatory cytokine up-regulation which in turn also activates the vascular endothelium. Through complex signaling, a positive feedback circuit is established which amplifies and sustains the activity of the inflammatory response resulting in the release of other cytokines and related molecules. If these responses are activated in an uncontrolled fashion with dissemination via the circulation, over the period of time, organs distant from the initial insult can be affected to produce multiple organ failure. Lactoferrin, an iron-binding glycoprotein, is considered an important mediator in host defense against the environmental insults in mammals. By virtue of iron sequestration lactoferrin can control the development of many oxidative stress-driven responses. The purpose of this review is to provide a comprehensive summary of research regarding lactoferrin and its role in homeostasis.

Topics: Animals; Humans; Inflammation; Lactoferrin

Homeostasis is the maintenance of equilibrium in a biological system by means of positive and negative feedback control mechanisms that counteract influences tending toward physiological dissonance. At the molecular level, homeostasis is controlled by the network of the neuro-endocrine-immune system, in which lactoferrin (LF) plays a central role. The purpose of this review is to provide a comprehensive summary of a collaborative study established between the Hirszfeld Institute of Immunology and Experimental Therapy (Wrocław, Poland) and the University of Texas Health Science Center (Houston, USA) regarding LF and its role in homeostasis. In our studies we focused on the immunoregulatory functions of LF, both in vitro and in vivo. We investigated the immune status of individuals subjected to different insults, including experimental endotoxemia in mice and surgery in humans. We also studied a LF-dependent delayed type hypersensitivity (DTH) response to evaluate some of the mechanisms by which LF can effectively substitute an adjuvant in vaccine.

Topics: Adjuvants, Immunologic; Animals; Cytokines; Endotoxemia; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Inflammation; Intestinal Mucosa; Iron; Lactoferrin; Lipopolysaccharides; Reactive Oxygen Species

This paper reviews our current knowledge of the structure and function of the iron-binding protein lactoferrin. In particular, it attempts to relate the various proposed physiological functions of lactoferrin to its most characteristic biochemical properties, i.e. its ability to bind iron and its highly basic nature. The extent to which various physiological functions can be considered as definitely established is critically reviewed, and suggestions for future research are proposed.

Topics: Animals; Autoantibodies; Bacteria; Gene Expression Regulation; Humans; Inflammation; Iron; Lactoferrin; Neoplasms; Parasites; Viruses

Lactoferrin is a multifunctional member of the transferrin family of nonheme iron-binding glycoproteins. Lactoferrin is found at the mucosal surface where it functions as a prominent component of the first line of host defense against infection and inflammation. The protein is also an abundant component of the specific granules of neutrophils and can be released into the serum upon neutrophil degranulation. While the iron-binding properties were originally believed to be solely responsible for the host defense properties ascribed to lactoferrin, it is now known that other mechanisms contribute to the broad spectrum anti-infective and anti-inflammatory roles of this protein. In this article, current information on the functions and mechanism of action of lactoferrin are reviewed, with particular emphasis on the activities that contribute to this protein's role in host defense. In addition, studies demonstrating that lactoferrin inhibits allergen-induced skin inflammation in both mice and humans, most likely secondary to TNF-alpha (tumor necrosis factor alpha) production, are summarized. Collectively, these results suggest that lactoferrin functions as a key component of mammalian host defense at the mucosal surface.

Topics: Animals; Anti-Inflammatory Agents; Host-Parasite Interactions; Humans; Hypersensitivity; Immunity, Innate; Immunity, Mucosal; Inflammation; Lactoferrin

Lactoferrin is an iron-binding glycoprotein found in exocrine secretions of mammals and released from neutrophilic granules during inflammation. This review describes the biological roles of lactoferrin in host defence. Secreted lactoferrin exerts antimicrobial action either by chelation of iron or by destabilization of bacterial membranes. Furthermore, lactoferrin modulates the inflammatory process, mainly by preventing the release of cytokines from monocytes and by regulating the proliferation and differentiation of immune cells. Some of these activities are related to the ability of lactoferrin to bind lipopolysaccharides (LPS) with high affinity. Indeed, recent in vitro studies indicate that lactoferrin is able to compete with the LPS-binding protein for LPS binding and therefore to prevent the transfer of LPS to CD14 present at the surface of monocytes. Moreover, the prophylactic properties of lactoferrin against septicemia in vivo have been demonstrated. Taken as a whole, these observations strongly suggest that lactoferrin is one of the key molecules which modulate the inflammatory response.

Topics: Animals; Anti-Infective Agents; Humans; Inflammation; Lactoferrin; Lipopolysaccharides; Protein Conformation

Lactoferrin is an iron-binding glycoprotein found in milk, exocrine secretions of mammals, and in secondary granules from polymorphonuclear neutrophils. This review describes the wide spectrum of functions ascribed to lactoferrin, with special emphasis on the antimicrobial properties of this protein, and its derived peptides.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiviral Agents; Cattle; Complement Activation; Cytokines; Female; Gram-Negative Bacteria; Humans; Inflammation; Iron; Lactoferrin; Milk; Neutrophils; Polysaccharides; Tissue Distribution; Virulence

Several natural components abundant in the fluid phase of human breast-milk have been shown to be inhibitors of complement activation in vitro, particularly the classical pathway. These include lysozyme, lactoferrin, lactalbumin alpha and other ligand chelators, complement regulator proteins and other specific soluble inhibitors of complement activation. Their physiological significance probably resides in their ability to restrict in vivo complement activation to specialized (compartmentalized) sites on the cellular membrane structures in human milk, represented by the abundant surface area of the milk fat globule membranes. This would serve to prevent inflammatory-induced tissue damage of the delicate immature gastrointestinal tract of the newborn as well as the mammary gland itself. A number of recognized and potential inhibitors of complement activity in human milk and other biological fluids are hereby reviewed, with a proposal of their physiological significance.

Topics: Animals; Complement Inactivator Proteins; Female; Humans; Immunoglobulins; Infant, Newborn; Inflammation; Lactalbumin; Lactoferrin; Mammary Glands, Animal; Milk, Human; Muramidase

The gastrointestinal tract may be viewed as an ecologic system in which a balance between the host and bacterial flora exists. Two major host components appear to be involved in maintaining this balance. The first is a non-specific structural barrier provided by the epithelial layer of the gastrointestinal mucosae. The second component involves functional immunological elements found in the mucosal and submucosal compartments, e.g., gut associated lymphoid tissue. When gut integrity is disrupted by invasive pathogens or by trauma, a myriad of pro-inflammatory mediators are released from cells in the gut wall that exert actions in the tissue or gut lumen. One of these mediators is lactoferrin, and iron binding protein found in high concentration in most human exocrine secretions. Despite controversies on its physiological role, evidence is emerging that lactoferrin plays an important role in host defense against toxic metabolites and antigenic components of potential pathogens2-4. This manuscript is intended to provide an overview of work related to lactoferrin's modulatory roles in inflammation, and to present observations from experimental studies on the preservation of intestinal structure and function by lactoferrin during intestinal inflammation. The possibility that lactoferrin limits the autodestructive inflammatory responses presents a new alternative for the future management of systemic inflammation.

Topics: Animals; Humans; Inflammation; Intestinal Diseases; Lactoferrin; Mice

Neutrophil influx into tissues occurs in many diverse diseases and can be associated with both beneficial and injurious effects. We hypothesize that the stimulus for certain neutrophilic inflammatory responses can be reduced to a series of competing reactions for iron, with either a labile or reactive coordination site available, between host chelators and chelators not indigenous to that specific living system. The iron focuses the transport of host phagocytic cells through a metal catalyzed generation of oxidant sensitive mediators including cytokines and eicosanoids. Many of these products are chemotactic for neutrophils. We also postulate that the iron increases the activity of the phagocyte associated NADPH oxidoreductase in the neutrophil. The function of this enzyme is likely to be the generation of superoxide in the host's attempt to chemically reduce and dislodge the iron from its chelate complex. After the reoxidation of Fe2+ in an aerobic environment, Fe3+ will be coordinated by host lactoferrin released by the neutrophil. When complexed by this glycoprotein, the metal does not readily undergo oxidation/reduction and is safely transported to the macrophages of the reticuloendothelial system where it is stored in ferritin. Finally, we propose that the neutrophil will attempt to destroy the chelator not indigenous to the host by releasing granular contents other than lactoferrin. Inability to eliminate the chelator allows this sequence to repeat itself, which can lead to tissue injury. Such persistence of a metal chelate in the host may be associated with biomineralization, fibrosis, and cancer.

Topics: Animals; Fibrosis; Free Radicals; Humans; Inflammation; Iron; Iron Chelating Agents; Lactoferrin; NADH, NADPH Oxidoreductases; Neoplasms; Neutrophils; Oxidation-Reduction; Phagocytes

Iron is essential to all microorganisms. To obtain iron from the very low concentrations present in their environment, microorganisms have developed sophisticated mechanisms such as the siderophore system. As a primitive defense mechanism, humans have developed mechanisms to withhold iron from microorganisms. Iron-binding proteins such as transferrin, ferritin, and lactoferrin have a central role in human ferrokinetics. These iron-binding proteins also participate in the process of decreasing iron availability for the microorganisms. They do so by decreasing iron reutilization. Anemia of inflammation (previously called anemia of chronic disease) is seen in the setting of infectious, inflammatory, and neoplastic diseases. It results, in part, from changes in the intracellular metabolism of iron. Alterations of iron physiology seen in many clinical circumstances make excess iron available to microorganisms, thus enhancing their pathogenicity. Understanding the molecular basis of iron withholding by the human host, both in the absence of and during infection, and that of iron acquisition by microorganisms may provide us with new and innovative antimicrobial agents and vaccines.

Topics: Anemia; Bacteria; Bacterial Infections; Blood Transfusion; Carrier Proteins; Conalbumin; Deferoxamine; Diabetic Ketoacidosis; Ferritins; Hemochromatosis; Hemolysis; Humans; Inflammation; Iron; Iron-Binding Proteins; Lactoferrin; Transferrin; Transferrin-Binding Proteins

To evaluate the value of fecal leukocytes, fecal occult blood, fecal lactoferrin and combination of fecal leukocytes with clinical data in the workup of patients with inflammatory diarrhea.. A systematic literature search in all languages using MEDLINE (1970 to 1994), reference lists of articles primarily retrieved and of review articles and correspondence with experts in the field.. The search identified 2603 references, 81 of which were deemed relevant on the basis of prespecified selection criteria. Of these 25 contained sufficient data for further analysis and thus were finally included.. All data from the selected articles were extracted by one observer whereas the second reviewer checked these data for accuracy. True positive rates and false positive rates were calculated from each 2 x 2 table.. The study summarizes the diagnostic accuracy of the signaled tests as predictors of inflammatory diarrhea as defined by stool culture (the reference test). Plots of true positive rates against false positive rates demonstrated widely scattered points, indicating heterogeneity. A summary receiver operating characteristic curve was fitted to the data with the use of logistic transforms and weighted least squares linear regression. Of the 25 studies analyzed 38 data points were used to construct summary receiver operating characteristic curves for index tests.. Fecal lactoferrin was the most accurate index test. Fecal leukocytes showed the lowest performance as assessed by the area under the curve. Occult blood and combination of fecal leukocytes with clinical data yielded intermediate curves. A limited number of studies (fecal lactoferrin, and fecal leukocytes with clinical data) and methodologic flaws identified in the assessed studies must be solved in future primary studies to improve the usefulness of the metaanalytic approach used here.

Topics: Blood; Communicable Diseases; Diarrhea; False Negative Reactions; False Positive Reactions; Feces; Humans; Inflammation; Lactoferrin; Leukocytes

Cells of nearly all forms of life require well-defined amounts of iron for survival, replication and expression of differentiated processes. It has a central role in erythropoiesis but is also involved in many other intracellular processes in the tissues of the body. It is the fourth most abundant element in the Earth's crust and the most abundant transition metal in living organisms for which its characteristic chemistry endows it with a series of properties enabling it to fulfil certain biological reactions especially those involving redox mechanisms. It is involved in the transport of oxygen, in electron transfer, in the synthesis of DNA, in oxidations by oxygen (O2) and hydrogen peroxide (H2O2) and in many other processes maintaining normal structure and function of virtually all mammalian cells. Because an iron atom can exist in two valency states, ferrous and ferric, iron became the primordial partner of oxygen in evolution. However, as de Sousa et al. (1989) state, such long standing partnerships have to use protective devices to ensure that the toxicity of neither partner is expressed in the presence of the other. Here, we discuss this dangerous partnership and its relevance to inflammation. The main themes of this review are the known roles of iron in the generation of reactive oxygen intermediates and new developments, including iron and transcription and the reaction of iron with nitric oxide. We also consider the widening recognition of the importance of oxygen metabolites in hypoxia-reperfusion injury and disease of the skin and joint.

Topics: Animals; Antioxidants; Arthritis, Rheumatoid; Ferritins; Hemoglobins; Hemosiderin; Humans; Hypoxia; Inflammation; Iron; Iron Chelating Agents; Lactoferrin; Nitric Oxide; Oxidants; Reactive Oxygen Species; Reperfusion; Skin Physiological Phenomena; Transcription Factors; Transferrin

Topics: Biomarkers; Humans; Inflammation; Isoenzymes; Lactoferrin; Leukocyte Elastase; Pancreatic Elastase; Specimen Handling

Polyclonal antibodies were prepared to purified breast milk lactoferrin and used in an ELISA to measure plasma concentrations in investigations of various aspects of the inflammatory response. They were also used, in situ, to evaluate granulocyte lactoferrin content in disease states. The first series of studies addressed the putative role of lactoferrin in the pathogenesis of the hypoferremic, hyperferritinemic response to acute inflammation. Dissociation between the lactoferrin response and the iron related changes in rheumatoid arthritis and after alpha-interferon administration suggested that the relationship observed in acute and chronic bacterial infection may reflect coincidental effects of inflammatory cytokines. That lactoferrin does not mediate the inflammatory hypoferremic response was established by the finding that bone marrow transplant recipients, post-myeloablation, developed a hypoferremic response during septic episodes despite virtually undetectable plasma lactoferrin concentrations. The second series of investigations employed the plasma lactoferrin concentration as an index of granulocyte activation and function in a number of inflammatory conditions. Markedly increased initial plasma concentrations in acute pneumonia reflecting profound intravascular granulocyte activation were documented to predict sepsis related mortality. Plasma and granulocyte lactoferrin studies established that viral infection is associated with an acquired granulocyte lactoferrin deficiency. Plasma measurements indicated that asthmatics, even when clinically asymptomatic, have evidence of persistent granulocyte activation.

Topics: Animals; Antibodies; Arthritis, Rheumatoid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interferon-alpha; Iron; Lactoferrin; Milk, Human; Predictive Value of Tests

The formation of hydroxyl radical via the iron catalyzed Haber-Weiss reaction has been implicated in phagocyte-mediated microbicidal activity and inflammatory tissue injury. The fact that neutrophils contain lactoferrin and mononuclear phagocytes have the capacity to acquire exogenous iron has suggested that iron bound to lactoferrin may influence the nature of free radical products generated by these cells. Over the years the iron-lactoferrin complex has been heralded as both a promoter and inhibitor of hydroxyl radical formation. This manuscript is intended to provide an overview of work performed to date related to this controversy and to present results of a number of preliminary studies which shed further light on the role of lactoferrin in inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Bactericidal Activity; Endopeptidases; Free Radicals; Humans; Hydroxyl Radical; Inflammation; Iron; Lactoferrin; Lipopolysaccharides; Oxidants; Oxidation-Reduction; Phagocytes; Receptors, Cell Surface

Topics: Absorption; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Growth; Humans; Immunity, Cellular; Infant; Infant, Newborn; Infant, Premature; Inflammation; Intestine, Small; Iron; Lactoferrin; Milk, Human; Nutritional Physiological Phenomena; Receptors, Transferrin

Topics: Animals; Bacteria; Humans; Inflammation; Iron; Lactoferrin; Milk, Human

Topics: Animals; Antibody Formation; Electron Spin Resonance Spectroscopy; Ferric Compounds; Humans; Immunity, Cellular; Inflammation; Interleukin-8; Killer Cells, Natural; Lactoferrin; Receptors, Cell Surface

Lactoferrin and transferrin exhibit very similar structure and biochemical properties but they behave as two distinct antigens and their affinity for ferric ions is not of the same magnitude. The biological functions of lactoferrin are not all well understood. It has strong bacteriostatic properties, it plays a role as a regulator of human granulopoiesis and it is probably involved in the hyposideremia of acute inflammation. Measurement of lactoferrin was first applied in pancreatic juice or duodenal fluid as a diagnostic tool for pancreatic diseases. More recently plasma lactoferrin has been used as an index of total circulating neutrophil pool in hematological disorders and in uremic patients during hemodialysis. Its clinical usefulness is still discussed for the early diagnostic of infectious diseases.

Topics: Anti-Infective Agents; Granulocytes; Inflammation; Lactoferrin; Lactoglobulins; Transferrin

Lactoferrin (LF)--in various quantities--is present in human milk, secretions and polymorphonuclear neutrophils (PMN). LF's significance lies in its bacteriostatic effect on its environment. Probably it prevents bacterial uptake of iron, leads to damage of bacteria and during phagocytosis helps the organism to combat pathogens. Most likely it regulates iron absorption, and during inflammation it takes part in the plasma iron transport. LF is believed to play an important role in the regulation of granulopoiesis in the bone-marrow. From its biological effects it appears that plasma LF determinations may be useful in the clinical diagnosis of leukaemia and other malignant diseases, as well as in the study of iron metabolism.

Topics: Absorption; Animals; Biological Transport; Cell Division; Chronic Disease; Granulocytes; Humans; Inflammation; Iron; Kinetics; Lactoferrin; Lactoglobulins; Leukemia, Myeloid; Milk; Pancreatic Neoplasms; Pancreatitis

During the intrauterine period, the human immunologic system develops through a complex but orderly series of events. The functional capacity of the system remains incomplete, not only during prenatal life but also through much of infancy. Many of the factors not produced by the fetus or infant are provided by the mother. Systemic immunity is augmented by specific IgG antibodies from the placenta and mucosal immunity by a wide array of defense agents from human milk including sIgA antibodies, lactoferrin, lysozyme, other soluble factors with antimicrobial properties, and specifically adapted leukocytes. It appears that the defense of the infant and the maternal contribution to that defense are geared to protect principally by noninflammatory mechanisms. Although much has been discovered about the ontogeny of the human immunologic system and the maternal contributions to this immunity, much remains to be learned about the molecular controls of the system, the fate of the transported maternal factors, feedback mechanisms between the immunologic systems of the mother and infant and the precise effects of maternal factors upon the infant. Answers to these questions may lead to the development of immunizing agents which are better suited to the infant, mucosal immunogens fashioned to stimulate the production of protective SIgA antibodies in human milk, the provision of defense factors for serious infections in young infants, and ways to enhance the maturation of the immunologic system of the infant when that is desirable.

Topics: Antibody Formation; B-Lymphocytes; Complement System Proteins; Female; Fetus; Humans; Immune System; Immunity, Cellular; Immunity, Maternally-Acquired; Immunoglobulin A, Secretory; Infant, Newborn; Inflammation; Lactoferrin; Leukocytes; Milk, Human; Muramidase; Phagocytes; Pregnancy; T-Lymphocytes

Topics: Antigen-Presenting Cells; Antigens; Capillary Permeability; Cell Adhesion; Cell Membrane; Cell Movement; Culture Techniques; Cytoplasmic Granules; Endothelium; Glycoproteins; Humans; Inflammation; Interleukin-1; Isoelectric Point; Lactoferrin; Leukocytes; Lipoxygenase; Lymphocytes; Monocytes; Neutrophils; Phospholipases; Platelet Activating Factor; Platelet Adhesiveness

Phagocytosis begins with exocytosis--"extrarapid" discharge of bactericidal proteins and factors of permeability into the extracellular medium. A viewpoint was put forward on an "avalanch-like" character of the outcome of cationic proteins from leukocyte granules in inflammation and their participation in formation of a nonphagocytic type of resistance. In phagocytosis bacteria perish due to the myeloperoxidase system, lysozyme, lactoferin and nonenzymic cationic proteins. Hereditary deficit of the above-mentioned substances leads to intraleukocytic microbicidal insufficiency, a drastic decrease in the nonspecific resistance of the organism and to development of fatal granulomatous disease, and to other forms of pathology associated with genetic defects of the bactericidal systems of leukocytes.

Topics: Blood Bactericidal Activity; Blood Proteins; Cell Membrane Permeability; Cytoplasmic Granules; Exocytosis; Glucosephosphate Dehydrogenase Deficiency; Histones; Humans; Immunity; Immunologic Deficiency Syndromes; Inflammation; Lactoferrin; Microscopy, Phase-Contrast; Muramidase; Neutrophils; Peroxidase; Phagocytosis

Topics: Blood Proteins; Cytoplasm; Cytoplasmic Granules; Glucose; In Vitro Techniques; Inflammation; Lactates; Lactoferrin; Lysosomes; Muramidase; NADH, NADPH Oxidoreductases; Peroxidase; Phagocytes; Phagocytosis

Milk derivative bovine Lactoferrin (bLf), a multifunctional glycoprotein available in large quantities and recognized as safe, possesses high homology and identical functions with human Lactoferrin. There are numerous food supplements containing bLf which, however, can vary in its purity, integrity and, consequently, functionality. Here, we report on a clinical trial where bLf (100 mg two times/day) was orally administered before (Arm A) or during meals (Arm B) to pregnant women with hereditary thrombophilia and suffering from anemia of inflammation. A significant increase of the number of red blood cells (RBCs), hemoglobin (Hb), total serum iron (TSI) and serum ferritin (sFtn) levels, along with a significant decrease of interleukin-6 were detected after 30 days in Arm A, but not in Arm B, thus letting us to hypothesize that bLf inefficacy could be related to its degradation by digestive proteases. To verify this hypothesis, bLf was incubated in gastric juice collected before or after meals. An undigested or a digested profile was observed when bLf was incubated in gastric juice sampled before or after meals, respectively. These results can explain the beneficial effect observed when bLf is administered under fasting conditions, i.e. in the absence of active proteases.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Animals; Anti-Infective Agents; Cattle; Female; Gastric Juice; Humans; Inflammation; Iron; Lactoferrin; Pregnancy; Thrombophilia

Lactoferrin modulates mucosal immunity and targets mechanisms contributing to inflammation during human immunodeficiency virus disease. A randomized placebo-controlled crossover clinical trial of recombinant human (rh) lactoferrin was conducted among 54 human immunodeficiency virus-infected participants with viral suppression. Outcomes were tolerability, inflammatory, and immunologic measures, and the intestinal microbiome. The median age was 51 years, and the median CD4+ cell count was 651/µL. Adherence and adverse events did not differ between rh-lactoferrin and placebo. There was no significant effect on plasma interleukin-6 or D-dimer levels, nor on monocyte/T-cell activation, mucosal integrity, or intestinal microbiota diversity. Oral administration of rh-lactoferrin was safe but did not reduce inflammation and immune activation. Clinical Trials Registration: NCT01830595.

Topics: Antiretroviral Therapy, Highly Active; CD4-Positive T-Lymphocytes; Cross-Over Studies; Double-Blind Method; Female; Gastrointestinal Microbiome; HIV; HIV Infections; Humans; Immunity, Mucosal; Inflammation; Interleukin-6; Lactoferrin; Lymphocyte Activation; Male; Middle Aged; Recombinant Fusion Proteins; Viral Load

To evaluate the effect of tablets containing lactoferrin (LF) and lactoperoxidase (LPO) on gingival health and oral health-related quality of life in healthy adults.. Lactoferrin and LPO are host defense factors found in saliva that may contribute to oral health.. One hundred and fifty adults were randomly assigned to the administration of high-dose tablets (LF 60 mg/d, LPO 7.8 mg/d), low-dose tablets (LF 20 mg/d, LPO 2.6 mg/d), or placebo tablets for 12 weeks. The gingival index (GI) and plaque index (PlI) were measured at baseline and after 12 weeks. Oral health-related quality of life was assessed by the Oral Health Impact Profile (OHIP) at baseline and at 4, 8, and 12 weeks.. One hundred and nine healthy subjects were included in the efficacy analysis. In the high-dose group, the GI was significantly reduced after 12 weeks of treatment, and the reduction in GI in the high-dose group was significant compared with the placebo group. In both the high-dose group and the low-dose group, PlI showed a significant decrease at 12 weeks compared with baseline. The total OHIP score was significantly reduced at 12 weeks in the high-dose group. In addition, the OHIP functional limitation subscale displayed significant improvement in the high-dose groups compared with the placebo group at 12 weeks. No adverse reactions or serious adverse events related to the test tablets were observed in any of participants during the study, and the incidence of adverse events unrelated to the tablets did not differ significantly among the groups.. These results suggest that intake of tablets containing LF (60 mg/d) and LPO (7.8 mg/d) can potentially improve gingival inflammation and oral health-related quality of life in healthy adults.

Topics: Adult; Dental Plaque Index; Double-Blind Method; Female; Humans; Inflammation; Lactoferrin; Lactoperoxidase; Male; Middle Aged; Oral Health; Periodontal Index; Quality of Life; Tablets

Fecal biomarkers are used increasingly to monitor Crohn's disease (CD). However, the relative accuracy of different markers in identifying inflammation has been poorly evaluated. We evaluated fecal calprotectin (FC), lactoferrin (FL), and S100A12 (FS) using endoscopic validation in a prospective study of the progression of CD after intestinal resection.. Data were collected from 135 participants in a prospective, randomized, controlled trial aimed at preventing postoperative CD recurrence. Three hundred nineteen stool samples were tested for FC, FL, and FS preoperatively and 6, 12, and 18 months after resection. Colonoscopy was performed at 6 and/or 18 months. Endoscopic recurrence was assessed blindly using the Rutgeerts score. C-reactive protein (CRP) and Crohn's Disease Activity Index (CDAI) were assessed.. FC, FL, and FS concentrations were elevated preoperatively (median: 1347, 40.9, and 8.4 μg/g, respectively). At 6 months postoperatively, marker concentrations decreased (166, 3.0, 0.9 μg/g) and were higher in recurrent disease than remission (275 versus 72 μg/g, P < 0.001; 5.7 versus 1.6 μg/g, P = 0.007; 2.0 versus 0.8 μg/g, P = 0.188). FC > 135 μg/g, FL > 3.4 μg/g, and FS > 10.5 μg/g indicated endoscopic recurrence (score ≥ i2) with a sensitivity, specificity, and negative predictive value (NPV) of 0.87, 0.66, and 91%; 0.70, 0.68, and 81%; 0.91, 0.12, and 71%, respectively. FC and FL correlated significantly with the presence and severity of endoscopic recurrence, whereas FS, CRP and CDAI did not.. FC was the optimal fecal marker for monitoring disease activity in postoperative CD and was superior to CRP and CDAI. FL offered modest sensitivity for detecting recurrent disease, whereas S100A12 was sensitive but had low specificity and NPV.

Topics: Adult; Biomarkers; C-Reactive Protein; Colonoscopy; Crohn Disease; Disease Progression; Endoscopy; Feces; Female; Follow-Up Studies; Humans; Inflammation; Inflammation Mediators; Lactoferrin; Leukocyte L1 Antigen Complex; Male; Middle Aged; Postoperative Period; Prognosis; Prospective Studies; Recurrence; Remission Induction; Severity of Illness Index

Leukocytes play a vital role in the host defence and inflammatory systems, the latter being responsible for the pathogenesis of a wide spectrum of acute and chronic diseases. Green tea is a popular beverage, which is consumed worldwide and its active ingredients are epicatechin derivatives, which possess distinct anti-inflammatory properties. The purpose of this study was to investigate if a green tea extract could enhance leukocyte function in humans.. Volunteers were asked to take 300 mg of the green tea extract daily for 14 days and the capacity of circulating leukocytes to release both myeloperoxidase and lactoferrin was assessed. Whole blood from volunteers was stimulated with the bacterial peptide Formyl-Methionine-Leucine-Phenylalanine (fMet-Leu-Phe). Myeloperoxidase an enzyme that converts hydrogen peroxide to hypochlorous acid and is stored and secreted from the granules of neutrophils and monocytes and was measured as well as lactoferrin which is an iron-binding protein stored and secreted from the neutrophils. In conjunction the antioxidant capacity of the blood of the volunteers was also determined using a chemiluminescence method that measures the capacity of plasma to scavenge superoxide.. After 14 days of treatment there was a significant increase in the release of myeloperoxidase and lactoferrin when whole blood was stimulated with fMet-Leu-Phe (p<0.05), which activates a number of leukocytes including mature neutrophils and monocytes. This was mirrored by a significant increase in the total antioxidant status after 14 days of green tea ingestion (p0.05). After the "wash-out" period of 4 weeks, all parameters were consistent with those observed at the start of the trial (day 0). Treatment with the green tea extract also caused a slight but non-significant decrease in the number of circulating leukocytes, but the counts remained within published "normal" ranges for healthy human adults.. This study indicates that a green tea extract when taken as a dietary supplement for 14 days can increase the leukocyte activity and the total plasma antioxidant status and may have role to play in the prevention of inflammatory disease.

Topics: Adult; Anti-Inflammatory Agents; Antioxidants; Camellia sinensis; Catechin; Dietary Supplements; Female; Humans; Inflammation; Lactoferrin; Leukocytes; Male; Middle Aged; Monocytes; Neutrophils; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Superoxides; Young Adult

This study evaluates the effects of retinol on intestinal barrier function, growth, total parasites, and Giardia spp infections in children in northeastern Brazil.. The study was a double-blind, randomized placebo-controlled trial (http://clinicaltrials.gov; register no. #NCT00133406) involving 79 children who received vitamin A 100,000-200,000 IU (n = 39) or placebo (n = 40) at enrollment, 4, and 8 months and were followed for 36 months. Intestinal barrier function was evaluated using the lactulose:mannitol ratio test. Stool lactoferrin was used as a marker for intestinal inflammation.. The groups were similar with regard to age, sex, nutritional parameters (z scores), serum retinol concentrations, proportion of lactoferrin-positive stool samples, and intestinal barrier function. The lactulose:mannitol ratio did not change during the same time of follow-up (P > 0.05). The proportion of lactoferrin-positive samples evaluated at 1 month did not change between groups (P > 0.05). Total intestinal parasitic, specifically new, infections were significantly lower in the vitamin A treatment compared with control group; these were accounted for entirely by significantly fewer new Giardia infections in the vitamin A treatment group. The cumulative z scores for weight-for-length or height, length or height-for-age z scores, and weight-for-age did not change significantly with vitamin A intervention for 36 months of follow-up.. These data showed that total parasitic infection and Giardia spp infections were significantly lower in the vitamin A treatment group when compared with the placebo group, suggesting that vitamin A improves the host's defenses against Giardia infections.

Topics: Adjuvants, Immunologic; Biomarkers; Child; Child, Preschool; Dietary Supplements; Double-Blind Method; Feces; Female; Giardiasis; Growth; Humans; Inflammation; Intestinal Mucosa; Lactoferrin; Male; Protozoan Infections; Vitamin A; Vitamins

A 6-month, randomized clinical study was conducted to evaluate the effect of a ribonuclease-enriched lactoferrin (R-ELF) supplement on the circulating cytokine levels and bone health of postmenopausal women.. Thirty-eight healthy postmenopausal women, aged 45-60 years, were randomized into placebo and R-ELF groups.. The R-ELF group was supplemented with R-ELF (2 × 125 mg/day) and calcium (100% RDA), while the placebo group received only the calcium supplement.. Serum levels of receptor activator for NF-κB ligand (RANKL), C-reactive protein (CRP) and various pro- and anti-inflammatory cytokines were determined by ELISA.. Pro-inflammatory cytokines IL-6 and TNF-α decreased significantly (-44 and -10%, respectively) while anti-inflammatory IL-10 increased (140%) due to R-ELF supplementation at the end of study. RANKL and CRP were modestly reduced (-50%) relative to their placebo levels, although RANKL elevated initially.. R-ELF supplementation showed beneficial effects towards improvement of inflammatory status in postmenopausal women.

Topics: Animals; Cattle; Cytokines; Dietary Supplements; Female; Humans; Inflammation; Lactoferrin; Middle Aged; Milk; Placebos; Postmenopause; Ribonucleases

Lactoferrin, a whey milk protein after removing precipitated casein, has a prominent activity against inflammation in vitro and systemic effects on various inflammatory diseases have been suggested. The objective was to determine dietary effects of lactoferrin-enriched fermented milk on patients with acne vulgaris, an inflammatory skin condition.. Patients 18 to 30 y of age were randomly assigned to ingest fermented milk with 200 mg of lactoferrin daily (n = 18, lactoferrin group) or fermented milk only (n = 18, placebo group) in a 12-wk, double-blind, placebo-controlled study. Acne lesion counts and grade were assessed at monthly visits. The condition of the skin by hydration, sebum and pH, and skin surface lipids was assessed at baseline and 12 wk.. Acne showed improvement in the lactoferrin group by significant decreases in inflammatory lesion count by 38.6%, total lesion count by 23.1%, and acne grade by 20.3% compared with the placebo group at 12 wk. Furthermore, sebum content in the lactoferrin group was decreased by 31.1% compared with the placebo group. The amount of total skin surface lipids decreased in both groups. However, of the major lipids, amounts of triacylglycerols and free fatty acids decreased in the lactoferrin group, whereas the amount of free fatty acids decreased only in the placebo group. The decreased amount of triacylglycerols in the lactoferrin group was significantly correlated with decreases in serum content, acne lesion counts, and acne grade. No alterations in skin hydration or pH were noted in either group.. Lactoferrin-enriched fermented milk ameliorates acne vulgaris with a selective decrease of triacylglycerols in skin surface lipids.

Topics: Acne Vulgaris; Adolescent; Adult; Animals; Cultured Milk Products; Double-Blind Method; Food, Fortified; Humans; Inflammation; Lactoferrin; Lipids; Sebum; Severity of Illness Index; Skin; Young Adult

The anti-inflammatory potential of azithromycin in chronic obstructive pulmonary disease (COPD) patients was explored following a standard oral dosing regimen. Patients with moderate and severe COPD were treated with azithromycin (500 mg, n=16) or placebo (n=8) once daily for 3 days in a randomized, double blind design, to compare effects on inflammation markers with those seen in a previous study in healthy volunteers. A battery of tests was made on serum, blood neutrophils and sputum on days 1 (baseline), 3, 4, 11, 18 and 32. In comparison to placebo, azithromycin resulted in an early transient increase in serum nitrites plus nitrates (day 3), associated with a tendency towards an increase in the blood neutrophil oxidative burst to phorbol myristic acetate. Subsequently, prolonged decreases in blood leukocyte and platelet counts, serum acute phase protein (including C reactive protein) and soluble E-selectin and blood neutrophil lactoferrin concentrations and a transient decrease in serum interleukin-8 were observed. Blood neutrophil glutathione peroxidase activity showed a prolonged increase after azithromycin treatment. The biphasic facilitatory-then-inhibitory response to azithromycin seen in healthy volunteers is not so clearly detectable in COPD patients, only potential anti-inflammatory effects. Treatment for longer periods may give therapeutic anti-inflammatory benefit in these patients.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azithromycin; Biomarkers; Blood Cell Count; C-Reactive Protein; Cell Count; Double-Blind Method; E-Selectin; Glutathione; Glutathione Peroxidase; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Humans; Inflammation; Interleukin-6; Interleukin-8; Lactoferrin; Male; Middle Aged; Neutrophils; Nitrates; Nitrites; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Respiratory Burst; Respiratory Function Tests; Serum Amyloid A Protein; Sputum; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Leucocytes have been shown to play a fundamental role in the pathophysiology of inflammation. This prospective, randomized, controlled study was designed to identify the most advantageous leucocyte depletion technique in terms of reduction in systemic inflammatory response syndrome and myocardial ischaemia reperfusion injury associated with cardiopulmonary bypass (CPB). Forty consecutive patients undergoing elective coronary artery bypass graft (CABG) surgery were randomly allocated to one of four groups. The four groups consisted of a control group, a systemic leucocyte depletion (SLD) group, a cardioplegic leucocyte depletion (CLD) group and a total leucocyte depletion (TLD) group. There were 10 patients in each group. Lactoferrin (marker of neutrophil activation) and troponin-I (marker of myocardial ischaemia reperfusion injury) were measured at six time points: post induction, 5 min on CPB, 5 min before releasing the aortic crossclamp, 15 min after releasing the clamp and 1 and 24 hours after the discontinuation of CPB. Plasma lactoferrin levels increased rapidly in every group after the commencement of CPB, subsequently reached a peak after releasing the aortic crossclamp and gradually declined after the discontinuation of CPB. The lowest lactoferrin concentration was observed in the TLD (range 2.15-141.9 ng/mL) and CLD groups (7.469-114.6 ng/mL). Regarding myocardial injury, plasma cardiac troponin-I levels did not differ significantly between groups; but troponin-I concentrations rose dramatically after releasing the aortic crossclamp in all groups. Nevertheless, the CLD group had the lowest troponin-I level (1.37-5.55 ng/mL). In conclusion, it is believed that myocardial ischaemia is probably a major contributor to the inflammatory response. Although there is no clear statistical significance shown in this pilot study, the data tend to support the cardioplegic leucocyte depletion strategy as the optimal method for attenuating neutrophil activation and myocardial ischaemia reperfusion injury.

Topics: Aged; Biomarkers; Cardiopulmonary Bypass; Equipment Design; Female; Filtration; Humans; Inflammation; Lactoferrin; Lymphocyte Depletion; Male; Middle Aged; Myocardial Reperfusion Injury; Neutrophil Activation; Treatment Outcome; Troponin I

The effects of aprotinin combined with heparin-bonded bypass circuits and reduced systemic heparinization on haemostasis and inflammatory reactions were measured in patients with elective CABG operation. Patients were randomized to be operated on either without aprotinin (NOAPRO, n=15) or with aprotinin (APRO, n=15) at a low dose of 2 Mio KIU in the priming volume. Activated clotting time was adjusted to 400 +/- 50 s during cardiopulmonary bypass (CPB). Haemostasis (fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), D-Dimer, plasmin-antiplasmin (PAP), plasminogen-activator inhibitor (PAI)), inflammatory reaction (lactoferrin, IL-6, sTNF-IIR, SC5b-9) and clinical data were evaluated perioperatively. Perioperative clinical and laboratory data including mediastinal drainage volume, postoperative morbidity and mortality were comparable for patients in both groups. FPA was elevated in the APRO group during CPB (P=0.001), D-Dimer in the NOAPRO group after CPB (P=0.002). No differences were seen for TAT, PAP or PAI between the groups. Lactoferrin was elevated in NOAPRO at the end of CPB (P=0.01) and after heparin reversal with protamine sulphate (P=0.02). No intergroup differences were seen for IL-6, sTNF-IIR or SC5b-9 between the groups. In association with reduced heparinization, pump prime aprotinin retains its antifibrinolytic effect in modified bypass equipment with a heparin surface besides an anti-inflammatory effect in terms of inhibition of leukocyte activation. However, thrombin activation may be increased with aprotinin. We therefore recommend sufficient systemic heparinization despite heparin surface modification of bypass equipment.

Topics: Aged; Aprotinin; Blood Coagulation; Cardiopulmonary Bypass; Female; Fibrinolysis; Hemostasis; Heparin; Humans; Inflammation; Lactoferrin; Male; Middle Aged; Myocardium; Time Factors

Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation.. The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1beta, TNF-alpha, or IL-8 in a mannose-binding lectin (MBL)-deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients.. The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Cell Adhesion Molecules; Chemokines; Complement Activation; Cytokines; Female; Humans; Inflammation; Lactoferrin; Male; Mannose-Binding Lectin; Middle Aged; Neutrophil Activation; Peroxidase; Plasma; Prospective Studies; Reperfusion Injury; Vascular Surgical Procedures

Cardiopulmonary bypass (CPB) is associated with the production of inflammatory responses, which can have significant influence on prognosis. We studied the effects of leucocyte-depletion filters on inflammatory parameters and early postoperative prognosis during coronary revascularization. Twenty patients undergoing elective coronary revascularization were randomly divided into two groups. Ten patients had leucocyte-depletion filters added to the CPB circuit (treatment group) and 10 were used as control cases (control group). Expression of CD11b on neutrophils, and production of myeloperoxidase and lactoferrin, were measured in arterial samples between induction and 3 h postbypass. In addition, clinical parameters were measured during inpatient recovery. CD11b neutrophil expression, and myeloperoxidase and lactoferrin production, were found to be upregulated during CPB and then to decline to preoperative levels by the third postoperative hour. Blood transfusion requirements were reduced in the treatment group, equalling 1.5 +/- 1.2 units, compared to 2.7 +/- 1.1 units for the control group (p value = 0.034) and so were the volumes of crystalloid infused during the first 24 h postoperatively, equalling 3.9 +/- 1.21 in the treatment group and 3.3 +/- 0.71 in the control group (p value = 0.021). Overall, the application of leucocyte depletion produced an early clinical advantage, underlining the need for an improved understanding and manipulation of the inflammatory response to CPB.

Topics: Biomarkers; Blood Loss, Surgical; Blood Transfusion; Cardiopulmonary Bypass; Crystalloid Solutions; Elective Surgical Procedures; Female; Filtration; Humans; Inflammation; Isotonic Solutions; Lactoferrin; Leukocyte Count; Leukocytes; Lymphocyte Depletion; Macrophage-1 Antigen; Male; Middle Aged; Myocardial Revascularization; Neutrophils; Peroxidase; Plasma Substitutes; Postoperative Period; Prognosis; Treatment Outcome

In some previous studies, the antihistamine cetirizine has inhibited both developing (at 6 hours) and established (at 24 hours) gross late-phase skin reactions (LPR) to pollen antigens, possibly relevant to clinical drug effects. However, the effects of cetirizine at the histologic level require further definition.. To characterize cetirizine effects on gross and histologic inflammatory events from 20 minutes to 24 hours after intradermal antigen challenge in sensitive patients.. Gross and histologic responses to intradermal pollen antigen, codeine, histamine, and buffer diluent were assessed during randomized 7-day treatments with cetirizine and placebo. Accumulated neutrophils, eosinophils, activated (EG2+) eosinophils, and T lymphocytes were quantitated. The degrees of extracellular deposition of lactoferrin from neutrophils and eosinophilic cationic protein (ECP) from eosinophils were also assessed.. During placebo treatment, wheal-and-flare responses were significantly greater to antigen at 20 minutes (p < 0.01) and induration at 6 hours (p < 0.01) at antigen challenge sites than at buffer diluent sites. During cetirizine treatment, these wheal-and-flare responses to antigen were inhibited significantly (p < 0.01) but gross LPRs were not affected. During placebo treatment, significantly more cells per high-power field were found in antigen sites than in buffer sites of neutrophils at 20 minutes (p < 0.01) and 24 hours; than in eosinophils at 20 minutes, 6 hours, and 24 hours (p < 0.01 for each); than in EG2+ cells at 20 minutes (p = 0.004), 6 hours (p = 0.001), and 24 hours (p = 0.02); and at T lymphocyte sites at 24 hours (p = 0.001). Extracellular deposition of lactoferrin and ECP was significantly greater at antigen sites than at buffer sites at 6 and 24 hours. Cetirizine treatment had no significant effect on these responses.. Neutrophils, eosinophils, and T lymphocytes were persistently more common at antigen sites than at buffer sites through 24 hours. Many of these neutrophils and eosinophils were activated, releasing more lactoferrin and ECP into the extracellular dermis for at least 24 hours after antigen challenge. Cetirizine inhibited gross immediate responses to antigen, but not the gross LPR nor the cellular inflammatory responses seen in such LPR sites.

Topics: Administration, Cutaneous; Anti-Allergic Agents; Biopsy; Blood Proteins; Cetirizine; Codeine; Eosinophil Granule Proteins; Eosinophils; Histamine; Humans; Hypersensitivity, Immediate; Inflammation; Lactoferrin; Leukocyte Count; Lymphocyte Count; Neutrophils; Pollen; Ribonucleases; Skin; Skin Tests; T-Lymphocytes

Effects of soluble recombinant human type I interleukin-1 receptor (sIL-1RI) were evaluated in 18 volunteers given intravenous endotoxin and randomized to placebo (n = 6), low-dose (n = 6), or high-dose (n = 6) sIL-1RI. Soluble IL-1RI decreased IL-1 beta (P = .001), but decreased IL-1ra (P = .0001), and resulted in 10-fold and 43-fold dose-related increases in sIL-1RI-IL-1ra complexes compared with placebo (P < or = .001). High-dose sIL-1RI was associated with increased levels of immunoactive tumor necrosis factor-alpha (P = .02), IL-8 (P = .0001), and cell-associated IL-1 beta (P = .047). C-reactive protein levels were higher after sIL-1RI than placebo (P = .035). Soluble IL-1RI decreased the severity of chills (P = .03), but did not alter other symptoms, changes in temperature, systemic hemodynamic responses, or changes in leukocyte and platelet number. Thus, sIL-1RI had no discernable antiinflammatory effect following endotoxin administration due in part to low levels of circulating IL-1 beta and neutralization of IL-1ra inhibitory function. This latter interaction represents an indirect mechanism of agonist activity elicited by sIL-1RI and may contribute to increases in inflammatory mediators, limiting therapy with sIL-1RI during endotoxemia.

Topics: Acute-Phase Reaction; Adult; Blood Cell Count; Cytokines; Endotoxins; Female; Fever; Gene Expression Regulation; Hemodynamics; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Lactoferrin; Male; Peptide Fragments; Receptors, Interleukin-1; Recombinant Fusion Proteins; Shivering; Sialoglycoproteins; Solubility; Tumor Necrosis Factor-alpha

The mechanisms explaining the beneficial effects of glucocorticoid in ventilator-dependent preterm infants are not known. In the present randomized trial, we evaluated the hypothesis that dexamethasone (DEX) treatment of small, preterm infants at risk for chronic lung disease favorably affects the surfactant system. Twenty-three ventilator-dependent infants, with a mean +/- SD gestational age of 26 +/- 2 wk and a mean birth weight of 836 +/- 173 g, received 1 wk of treatment with either DEX (dose 0.5 mg/kg/d) or placebo beginning at 2 wk of age. The airway specimens were analyzed for surfactant components, surface activity, surfactant inhibitors, and inflammatory mediators. The concentrations of these parameters in epithelial lining fluid were calculated using the urea method. DEX treatment decreased the concentration of nonsedimentable protein in epithelial lining fluid within 3 d (p < 0.05). The nonsedimentable fraction of airway specimens decreased the surface activity of surfactant as a function of protein concentration. At a constant protein concentration, the protein from placebo-treated infants inhibited the surface activity of human surfactant in vitro more than protein from DEX-treated infants (p < 0.05). DEX transiently increased the concentration of surfactant protein-A in epithelial lining fluid but had no effect on surface activity of the sedimentable surfactant complex or on concentrations of phosphatidylcholine, IL-1 beta, lactoferrin, or myeloperoxidase. We conclude that the acute beneficial effect of DEX treatment in preterm ventilator-dependent infants may in part be mediated through a decrease in the concentration of non-sedimentable protein and a decrease in the capacity of this protein to inhibit surface activity.

Topics: Blood Proteins; Chronic Disease; Dexamethasone; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Inflammation; Interleukin-1; Lactoferrin; Lung Diseases; Male; Peroxidase; Pulmonary Surfactants; Risk Factors; Trachea; Treatment Outcome

Chronic bronchitis is associated with airways obstruction and inflammation. In order to determine whether aerosolized beclomethasone can modulate airway inflammation and diminish airway obstruction, subjects with chronic bronchitis performed spirometry and underwent bronchoalveolar lavage (BAL) before and after receiving 6 wk of therapy (five puffs four times a day) with either aerosolized beclomethasone (n = 20) or placebo (n = 10) in a double-blinded, randomized fashion. All subjects received aerosolized albuterol before each use of the study medications. Before BAL, the airways were visually assessed for the appearance of inflammation and assigned a score, the bronchitis index. BAL was performed by instilling five 20-ml aliquots of saline into each of three sites and pooling and separately analyzing the returns from the first aliquots to yield a "bronchial sample." The bronchial lavages were repeated in an additional three sites to increase the volume of fluid available for analysis. The fluid was prepared for cytologic examination by cytocentrifugation. Albumin (as a measure of epithelium permeability) and lactoferrin and lysozyme (as measures of serous cell activity) were measured in unconcentrated BAL fluid by enzyme-linked immunosorbent assay, and concentrations in epithelial lining fluid were estimated using urea as an internal marker for dilution. After treatment, the beclomethasone group, but not the placebo group, showed improvement in FVC (p = 0.02), FEV1 (p = 0.002), and 25 to 75% forced expiratory flow (p = 0.006). Associated with the improvement in spirometry, the bronchitis index fell (13.5 +/- 1.0 versus 10.75 +/- 1.1, p = 0.02) in the beclomethasone-treated group, but not the placebo-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adult; Aerosols; Airway Obstruction; Albumins; Beclomethasone; Blood Gas Analysis; Bronchitis; Bronchoalveolar Lavage Fluid; Bronchoscopy; Chronic Disease; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Inflammation; Lactoferrin; Male; Middle Aged; Muramidase; Smoking; Transferrin; Vital Capacity

Lactoferrin (Lf), a multiple functional natural immune protein, is widely distributed in mammalian milk and glandular secretions (bile, saliva, tears and nasal mucosal secretions, etc.). In the previous study, we found that Lf plays an anti-inflammatory and anti-tumorigenesis role in AOM/DSS (azoxymethane/dextran sulfate sodium) induced mouse colitis-associated colon cancer model. Although we found that Lf has anti-inflammatory effects in chronic inflammation, its specific role and mechanisms in acute inflammation have not been clarified. Here, we reported that the expression levels of Lf were significantly increased when the organism was infected by Gram-negative bacteria. We then explored the role and potential mechanism of Lf in lipopolysaccharide (LPS)-induced acute inflammation. In the LPS-induced acute abdominal inflammation model, Lf deficiency aggravated inflammatory response and promoted macrophage chemotaxis to the inflammation site. Lf inhibited macrophage chemotaxis by suppressing the expression of macrophage-associated chemokines Ccl2 and Ccl5. Highly activated NF-κB signaling in Lf

Topics: Animals; Inflammation; Lactoferrin; Lipopolysaccharides; Macrophages; Mice; NF-kappa B

The aim of this study was to explore the anti-inflammatory and anti-lipid effects of lactoferrin on SZ95 human sebaceous gland cells and mouse model of acne.. SZ95 cells were co-cultured with different concentrations of lactoferrin, and cell viability was determined using the 2,5-diphenyl-2H-tetrazolium bromide method. Oil red O and Nile red staining were performed to determine the lipid content. The mRNA expression of genes related to lipid metabolism (sterol regulatory element-binding protein-1 [SREBP-1], fatty acid synthase [FAS], stearoyl-CoA desaturase-1 [SCD-1], fatty acid desaturase 2 [FADS2]) and inflammation (interleukin-8 [IL-8]) was determined by reverse transcription-polymerase chain reaction. An acne mouse model was established using injection of P. acnes on the backs of mice. The proliferation and apoptosis of sebaceous gland cells were examined by immunohistochemistry against proliferating cell nuclear antigen (PCNA) and TUNEL staining, respectively. Western blotting was used to detect FADS2 and CXCL15 protein expression.. Lactoferrin treatment at 10-500 μg/ml significantly decreased the lipid content, as revealed by the oil red O and Nile red staining. It also attenuated the increase of mRNA expression of SREBP-1, FAS, SCD-1, FADS2, and IL-8 in insulin-treated SZ95 cells. Moreover, lactoferrin treatment at the doses of 1-50 mg/mouse significantly reduced the inflammation and lipid production in the mouse model of acne. Also, the number of sebaceous gland cells was significantly reduced, and apoptosis was significantly increased by lactoferrin treatment in the mice. Mechanically, the levels of FADS2 and CXCL15 proteins in tissues were significantly decreased after lactoferrin treatment in the model mice.. Our results demonstrate the potential of lactoferrin against sebogenesis, sebaceous gland inflammation in acne.

Topics: Acne Vulgaris; Animals; Humans; Inflammation; Interleukin-8; Lactoferrin; Lipogenesis; Mice; RNA, Messenger; Sebaceous Glands; Sterol Regulatory Element Binding Protein 1

Immunoglobulin A (IgA) is mostly considered as a non-inflammatory regulator at mucosal areas. However, previous work of our group showed that IgA can also be involved in disease pathology, because it provides a potent stimulus to activate neutrophils after crosslinking of surface CD89 (FcaRI), resulting in chronic inflammation and tissue damage. IgA (auto)antibodies and neutrophils are key players in various diseases, including blistering skin diseases and rheumatoid arthritis. Therefore, we generated an array of anti-CD89 monoclonal antibodies (mAbs) for therapeutic targeting of CD89. The biological activity of newly developed anti-human CD89 mAbs and their potential therapeutic capacity were investigated.. Human neutrophils were isolated from heparinized healthy donor blood. The ability of anti-CD89 mAbs to bind human neutrophils was investigated by flow cytometry. Furthermore, the capacity of these anti-CD89 mAbs to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and migration was studied. To this end, neutrophils were pre-incubated with/without anti-CD89 mAbs after which they were stimulated with IgA-coated beads. The amount of phagocytosed beads, NET release and migrated neutrophils were subsequently analysed. In parallel, chemoattractant leukotriene B4 and lactoferrin (as a measure for degranulation) release were determined. Finally, the therapeutic potential of our prototypic anti-CD89 mAb clone 10E7 was in vivo tested in anti-mouse collagen XVII human IgA-treated transgenic CD89 mice, a preclinical model for autoimmune linear IgA bullous disease (LABD).. Our results show that all generated anti-CD89 mAbs bound surface CD89 on neutrophils. Although these anti-CD89 mAbs bind to different epitopes on EC1 of CD89, they all have the capacity to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and neutrophil migration. Moreover, IgA mediated leukotriene B4 and lactoferrin release are decreased in supernatant from anti-CD89 mAbs-treated neutrophils. Finally, anti-CD89 mAb clone 10E7, that was selected based on its selective binding profile on tissue micro arrays, reduced anti-mouse collagen XVII hIgA-induced neutrophil influx in an in vivo linear IgA bullous disease (LABD) mice model.. This study clearly indicates that our newly developed anti-CD89 mAbs inhibited IgA-induced neutrophil activation and reduced anti-autoantigen IgA-induced neutrophil influx in vivo, supporting further clinical development for the treatment of LABD.

Topics: Animals; Autoimmunity; Immunoglobulin A; Inflammation; Lactoferrin; Leukotriene B4; Mice

The impact of lactoferrin, an antimicrobial peptide (AMP) with iron-binding properties, on the intestinal barrier and microflora of mice infected with highly pathogenic avian influenza A (H5N1) virus remains unclear. To investigate the effects of lactoferrin on the histopathology and intestinal microecological environment, we conducted a study using H5N1-infected mice. H5N1 infection resulted in pulmonary and intestinal damage, as well as an imbalance in gut microbiota, significantly increasing the abundance of pathogenic bacteria such as

Topics: Animals; Bacteria; Gastrointestinal Microbiome; Inflammation; Influenza A Virus, H5N1 Subtype; Intestinal Diseases; Intestines; Lactoferrin; Mice

Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic properties and has been shown to protect very immature brains against HI damage. We hypothesized that combining early oral administration of LF with whole body hypothermia could enhance neuroprotection in a HIE rat model. Pregnant Wistar rats were fed an LF-supplemented diet (1 mg/kg) or a control diet from (P6). At P7, the male and female pups had the right common carotid artery occluded followed by hypoxia (8% O

Topics: Animals; Animals, Newborn; Brain; Female; Hypothermia; Hypoxia-Ischemia, Brain; Inflammation; Lactic Acid; Lactoferrin; Male; Neuroprotective Agents; Rats; Rats, Wistar; RNA, Messenger

Infection with Mycobacterium tuberculosis (Mtb) results in the primary formation of a densely packed inflammatory foci that limits entry of therapeutic agents into pulmonary sites where organisms reside. No current therapeutic regimens exist that modulate host immune responses to permit increased drug penetration to regions of pathological damage during tuberculosis disease. Lactoferrin is a natural iron-binding protein previously demonstrated to modulate inflammation and granuloma cohesiveness, while maintaining control of pathogenic burden. Studies were designed to examine recombinant human lactoferrin (rHLF) to modulate histological progression of Mtb-induced pathology in a non-necrotic model using C57Bl/6 mice. The rHLF was oral administered at times corresponding to initiation of primary granulomatous response, or during granuloma maintenance. Treatment with rHLF demonstrated significant reduction in size of primary inflammatory foci following Mtb challenge, and permitted penetration of ofloxacin fluoroquinolone therapeutic to sites of pathological disruption where activated (foamy) macrophages reside. Increased drug penetration was accompanied by retention of endothelial cell integrity. Immunohistochemistry revealed altered patterns of M1-like and M2-like phenotypic cell localization post infectious challenge, with increased presence of M2-like markers found evenly distributed throughout regions of pulmonary inflammatory foci in rHLF-treated mice.

Topics: Animals; Fluoroquinolones; Granuloma; Humans; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis

Inflammation is the body's response to injury or infection and is important for healing and eliminating pathogens; however, prolonged inflammation is damaging and may lead to the development of chronic inflammatory disorders. Recently, there has been interest in exploiting antimicrobial peptides (AMPs) that exhibit immunoregulatory activities to treat inflammatory diseases.. In this study, we investigated the immunomodulatory effects of lactoferrin-derived lactoferricin AMPs from three different species (bovine, mouse, and human) with subtle differences in their amino acid sequences that alter their antimicrobial action; to our knowledge, no other studies have compared their immunomodulatory effects. Macrophages, key players in the induction and propagation of inflammation, were used to investigate the effects of species-specific lactoferricin peptides on inflammatory processes.. Bovine lactoferricin was the only one of the three peptides studied that downregulated lipopolysaccharide (LPS)-induced pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6, in both human and mouse macrophages. Lactoferricin regulated inflammation through targeting LPS-activated nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Although the immunoregulatory role of lactoferricin during an inflammatory response. The ability of lactoferricin, especially that of bovine origin, to downregulate macrophage-mediated inflammatory responses suggests potential for the development of this peptide as a novel immunotherapeutic agent in the treatment of chronic inflammatory conditions.

Topics: Animals; Cattle; Cytokines; Humans; Inflammation; Lactoferrin; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Peptides

Infant intestinal development is immature and, thus, is vulnerable to bacterial and viral infections, which damage intestinal development and even induce acute enteritis. Numerous studies have investigated that lactoferrin (LF) has protective effects on the intestine and may play a role in preventing intestinal inflammation in infants. Lactoferrin is divided into 2 types, namely apo-LF and holo-LF, depending on the degree of iron saturation, which may affect its bioactivities. However, the role of LF iron saturation in protecting infant intestinal inflammation has not been clearly clarified. Therefore, in this study, young mice models with intestinal damage induced by lipopolysaccharides (LPS) in vivo and primary intestinal epithelial cells in vitro were constructed to enteritis injury in infants for investigation. The apo-LF and holo-LF were subsequently applied to the mouse models to investigate and compare their levels of protection in the intestinal inflammatory injury, as well as to identify which LF was most active. Moreover, the specific mechanism of the LF with optimal iron saturation was further investigated through Western blot assay. Results demonstrated that disease activity index, shortened length of colon tissue, and histopathological score were significantly decreased in the apo-LF group compared with those of the LPS group and the holo-LF group. In the apo-LF group, the concentration of LPS in the intestinal tract and the number of gram-negative bacteria colonies decreased significantly and the expression levels of proinflammatory factors in the colon tissue were downregulated, in comparison with those in the LPS group. The findings of this study thus verify that apo-LF can significantly alleviate enteritis injury caused by LPS, through regulating the PPAR-γ/PFKFB3/NF-κB inflammatory pathway.

Topics: Animals; Enteritis; Inflammation; Iron; Lactoferrin; Lipopolysaccharides; Mice; Recombinant Proteins

Cystic Fibrosis (CF) has prominent gastrointestinal and pancreatic manifestations. The aim of this study was to determine the effect of Cystic fibrosis transmembrane conductance regulator (CFTR) modulation on, gastrointestinal inflammation, pancreatic function and gut microbiota composition in people with cystic fibrosis (CF) and the G551D-CFTR mutation.. Fourteen adult patients with the G551D-CFTR mutation were assessed clinically at baseline and for up to 1 year after treatment with ivacaftor. The change in gut inflammatory markers (calprotectin and lactoferrin), exocrine pancreatic status and gut microbiota composition and structure were assessed in stool samples.. There was no significant change in faecal calprotectin nor lactoferrin in patients with treatment while all patients remained severely pancreatic insufficient. There was no significant change in gut microbiota diversity and richness following treatment.. There was no significant change in gut inflammation after partial restoration of CFTR function with ivacaftor, suggesting that excess gut inflammation in CF is multi-factorial in aetiology. In this adult cohort, exocrine pancreatic function was irreversibly lost. Longer term follow-up may reveal more dynamic changes in the gut microbiota and possible restoration of CFTR function.

Topics: Adult; Aminophenols; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Inflammation; Lactoferrin; Leukocyte L1 Antigen Complex; Microbiota; Mutation; Prospective Studies; Quinolones

Dry eye disease (DED) is a complex ocular surface inflammatory disease. Its occurrence varies widely over the world, ranging from 5% to 34%. The use of preservatives, specifically benzalkonium chloride, in the ocular drops worsens the DED conditions. Furthermore, the Covid-19 pandemic increased screen time and the use of face masks and shields. As a result, the number of people suffering from dry eye disease (DED) has increased significantly in recent years. The main objective of our study is to find a solution to manage the dry eye disease (DED) preferably from natural source without any adverse events. In this study, the beneficial effects of capsanthin from Capsicum annum (CCA) were evaluated on benzalkonium chloride (BAC)-induced dry eye disease (DED) in Albino Wistar rats. Oral supplementation of CCA resulted in a statistically significant decrease in intraocular pressure (IOP) (p < .0001), increase in tear break-up time (TBUT) (p < .01), decline in Schirmer test results (p < .01), and decrease in corneal surface inflammation (p < .01). Capsanthin ameliorated in reducing oxidative stress by increasing serum antioxidant levels such as glutathione peroxidase (GPX), nitric oxide (NO), and lactoferrin (LTF) and inhibiting matrix metalloproteinases 2 and 9 (MMP2 and MMP9) (p < .0001). Capsanthin treatment significantly inhibited the expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukins (IL-2, IL-4, IL-6), and pro-inflammatory mediator, matrix metalloproteinase-9 (MMP9). Furthermore, the lacrimal gland expressed vascular cell adhesion molecule (VCAM-1), and prostaglandin-endoperoxide synthase 2 (PTGS2) was suppressed by CCA treatment. PRACTICAL APPLICATIONS: Benzalkonium chloride (BAC), a preservative widely used in the topical ocular drug delivery system (ODDS), causes undesirable effects such as dry eye disease as well as ameliorating intraocular pressure leading to optical nerve damage and irreversible vision loss. Capsanthin from Capsicum annum (CCA) can be used to treat symptoms related to dry eye disease such as inflammation, eye irritation, visual disturbance, ocular discomfort with potential damage to the ocular surface. The CCA may be beneficial in the treatment of glaucoma, an elevated intraocular pressure. Capsanthin from C. annum can be useful in managing DED by increasing tear break-up time (TBUT), declining in Schirmer test results and decreasing in corneal surface inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Benzalkonium Compounds; Capsicum; COVID-19; Cyclooxygenase 2; Cytokines; Dry Eye Syndromes; Fruit; Gene Expression; Glutathione Peroxidase; Humans; Inflammation; Inflammation Mediators; Interleukin-2; Interleukin-4; Interleukin-6; Lactoferrin; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nitric Oxide; Pandemics; Rats; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Xanthophylls

Ready-to-feed liquid infant formula is increasingly used for preterm infants when human milk is unavailable. These formulas are sterilized by ultra-high temperature treatment, but heating and storage may reduce bioactivity and increase formation of Maillard reaction products with potential negative consequences for immature newborns.. Using preterm pigs as a model for sensitive newborn infants, the study tests the intestinal responses of feeding experimental liquid formula within 5 days. A pasteurized formula (PAST) with the same nutrient composition but less protein modifications serves as control to ultra-high temperature-treated formula without (UHT) and with prolonged storage (SUHT). Relative to PAST, UHT contains lower levels of lactoferrin and IgG. Additional storage (40 °C, 60 days, SUHT) reduces antimicrobial capacity and increases non-reducible protein aggregates and Maillard reaction products (up to 13-fold). Pigs fed SUHT have more diarrhea and show signs of intestinal inflammation (necrotizing enterocolitis) compared with pigs fed PAST and UHT. These clinical effects are accompanied by accumulation of Maillard reaction products, protein cross-links, and inflammatory responses in the gut.. The results demonstrate that feeding UHT infant formulas, particularly after prolonged storage, adversely affects gut maturation and function in preterm pigs used as a model of preterm infants.

Topics: Animals; Animals, Newborn; Glycation End Products, Advanced; Humans; Immunoglobulin G; Infant; Infant Formula; Infant, Newborn; Infant, Premature; Inflammation; Intestines; Lactoferrin; Protein Aggregates; Swine; Temperature

Milk lactoferrin is a multi-functional, iron-binding glycoprotein with immunomodulatory effects, protecting infants against infectious diseases.. This study explored how maternal inflammation/infection and iron-deficiency anemia (IDA) might influence human milk lactoferrin. Lactoferrin might be elevated with maternal inflammation resulting from infectious disease processes. Conversely, lactoferrin might decrease with IDA, corresponding to scarce maternal iron for transfer in milk. In these two hypothesized scenarios, the degree of lactoferrin elevation or decrease might vary with infant vulnerability to infectious diseases or malnutrition. Alternatively, lactoferrin might be unassociated with inflammation/infection or IDA if mothers could buffer it against these conditions.. We used cross-sectional data from Ariaal mothers of northern Kenya (n = 200) to evaluate associations between milk lactoferrin and maternal inflammation/infection, IDA, infant age/sex, and the mother-infant variable interactions in multivariate regression models.. Maternal inflammation was associated with higher lactoferrin for younger infants (<~5 months of age) but with lower lactoferrin for older infants. Maternal IDA was unassociated with lactoferrin alone or in interaction with infant variables.. Results suggest that mothers of vulnerable young infants deliver more lactoferrin when they have inflammation/infection but mothers with older infants do not, and that maternal delivery of lactoferrin is unaffected by their IDA. Longitudinal research should verify these findings.

Topics: Anemia, Iron-Deficiency; Communicable Diseases; Cross-Sectional Studies; Female; Humans; Infant; Inflammation; Iron; Iron Deficiencies; Kenya; Lactoferrin; Milk, Human

The use of cyclophosphamide (CP) as a chemotherapeutic agent is limited by its major complication haemorrhagic cystitis (HC). Finding preventive, safe, and efficient treatments for such problems is extensively ongoing.. This research aims to assess the uroprotective effect of pramipexole (PPX) and/or lactoferrin (LF) against CP-induced HC, in addition to shedding light on their possible molecular targets.. Adult male Sprague-Dawley rats were orally administered PPX (3 mg/kg) and/or LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg).. Pretreatment of CP-intoxicated rats with either PPX or LF mitigated oxidative urinary bladder damage via upregulation of the Nrf2/HO-1 signalling pathway, resulting in a significant reduction in bladder MDA and 8-OHdG levels with concomitant elevations in SOD activity and GSH content. Simultaneously, both drugs markedly halted inflammation in bladder tissue through inhibition of the TLR4/NF-κB signalling pathway, followed by a significant decrease in inflammatory cytokine levels (TNF-α and IL-6). Interestingly, the PPX/LF protocol downregulated p-p38, p-ERK1/2, Sphk1, and S1P protein expression and inhibited the NLRP3/caspase1/IL-1β axis. PPX/LF also significantly reduced BAX and caspase-3, in addition to increasing Bcl-2 levels in bladder tissue of CP-treated animals. These biochemical findings were supported by the improvement in the histological alterations induced by CP in the urinary bladder.. The current study verified the protective effect of PPX and LF against CP-induced HC by halting oxidative stress, inflammation, and apoptosis. The molecular mechanism underlying this protective effect may involve targeting the crosstalk among Sphk1/S1P/MAPK/NF-κB, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1β signalling pathways and modulating the Nrf2/HO-1 signalling pathway.

Topics: Animals; bcl-2-Associated X Protein; Caspase 1; Caspase 3; Cyclophosphamide; Cystitis; Cytokines; Inflammation; Interleukin-6; Lactoferrin; Male; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pramipexole; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Inflammation may contribute to excess mortality in rheumatoid arthritis (RA) patients. We investigated associations to all-cause mortality of the inflammation markers high-sensitivity C-reactive protein (CRP), lactoferrin (neutrophil activation marker), and neopterin (monocyte activation marker). From the population-based Trøndelag Health Study (3rd wave 2006-2008), 316 RA patients and 43,579 controls were included. Lactoferrin and neopterin were quantified in a nested cohort (n = 283 RA patients, n = 3698 controls). Follow-up was until death found by linkage to the Norwegian Cause of Death Registry or 31.12.2018. All-cause mortality was analyzed using Cox regression and Cox regression-based mediation analysis. Having RA (hazard ratio (HR): 1.25, 95%CI: 1.00, 1.56, p = 0.048), and CRP ≥ 3 mg/L (HR: 1.50, 95%CI: 1.41, 1.60, p < 0.001) were associated with all-cause mortality. The overall excess relative mortality risk of having RA was 38%. CRP ≥ 3 mg/L mediated approximately 1/4 of this risk (p < 0.001). In the nested cohort, CRP ≥ 3 mg/L (HR: 1.51, 95%CI: 1.26, 1.80, p < 0.001) and neopterin (HR: 1.17, 95%CI: 1.01, 1.36, p = 0.031) were associated with all-cause mortality. In conclusion, CRP levels ≥ 3 mg/L mediated approximately a quarter of the 38% excess relative all-cause mortality risk associated with RA. Using definitions of RA remission with emphasis both on joint status and the level of general inflammation may help guide the most efficient treatment regimens.

Topics: Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Humans; Inflammation; Lactoferrin; Neopterin; Proportional Hazards Models; Risk Factors

Chronic endometritis (CE) is a type of chronic inflammation in the endometrium that is associated with infertility, which is primarily due to implantation failure. Antibiotics are the most common treatment for CE. However, some patients with CE are resistant to antibiotic treatment, while others refuse this treatment. Therefore, we focused on lactoferrin (Lf), which exhibits antimicrobial and anti-inflammatory properties, and studied its effect on inflammation in endometrial stromal cells (ESCs) from patients with CE. Endometrial tissue was collected from patients with CE, and ESCs were isolated and cultured. When ESCs were cultured with bovine lactoferrin (bLf: 1 mg/mL), the mRNA expression of TNF-α (p < 0.05) and IL-1β (p < 0.01) was significantly decreased compared with that in cells cultured without bLf. The level of TNF-α protein in the culture medium was significantly decreased (p < 0.01), while that of IL-1β was also decreased, but not significantly (p < 0.10), when 1 mg/mL of bLf was added to the culture medium. When more inflammation was induced artificially by adding 0.1 ng/mL of TNF-αto ESCs, the addition of bLf (1 mg/mL) to ESCs decreased IL-6 and IL-1β mRNA expression to levels similar to those in ESCs without TNF-α treatment. Furthermore, it was revealed that the actions of bLf are mediated by the AKT and MAPK intracellular signaling pathways, which are mechanisms by which the increase in TNF-α-induced cytokine expression is suppressed in ESCs. bLf suppresses the expression of inflammatory cytokines in human ESCs and may be a new therapeutic candidate for CE.

Topics: Anti-Bacterial Agents; Chronic Disease; Cytokines; Endometritis; Female; Humans; Inflammation; Lactoferrin; RNA, Messenger; Stromal Cells; Tumor Necrosis Factor-alpha

Deoxynivalenol (DON) is a major mycotoxin present in staple foods (particularly in cereal products) that induces intestinal inflammation and disrupts intestinal integrity. Lactoferrin (LF) is a multifunctional protein that contributes to maintaining intestinal homeostasis and improving host health. However, the protective effects of LF on DON-induced intestinal dysfunction remain unclear.. This study aimed to investigate the effects of LF on DON-induced intestinal dysfunction in mice, and its underlying protective mechanism.. Male BALB/c mice (5 wk old) with similar body weights were divided into 4 groups (n = 6/group) and treated as follows for 5 wk: Veh [peroral vehicle daily, commercial (C) diet]; LF (peroral 10 mg LF/d, C diet); DON (Veh, C diet containing 12 mg DON/kg); and LF + DON (peroral 10 mg LF/d, DON diet). Intestinal morphology, tight junction proteins, cytokines, and microbial community were determined. Data were analyzed by 2-factor ANOVA or Kruskal-Wallis test.. The DON group exhibited lower final body weight (-12%), jejunal villus height (VH; -41%), and jejunal occludin expression (-36%), and higher plasma IL-1β concentration (+85%) and jejunal Il1b mRNA expression (+98%) compared with the Veh group (P < 0.05). In contrast, final body weight (+19%), jejunal VH (+49%), jejunal occludin (+53%), and intelectin 1 protein expression (+159%) were greater in LF + DON compared with DON (P < 0.05). Additionally, jejunal Il1b mRNA expression (-31%) and phosphorylation of p38 and extracellular signal regulated kinase 1/2 (-40% and - 38%) were lower in LF + DON compared with DON (P < 0.05). Furthermore, the relative abundance of Clostridium XIVa (+181%) and colonic butyrate concentration (+53%) were greater in LF + DON compared with DON (P < 0.05).. Our study highlights a promising antimycotoxin approach using LF to alleviate DON-induced intestinal dysfunction by modulating the mitogen-activated protein kinase pathway and gut microbial community in mice.

Topics: Animals; Gastrointestinal Microbiome; Inflammation; Intestinal Diseases; Lactoferrin; Male; MAP Kinase Signaling System; Mice; Occludin; RNA, Messenger; Trichothecenes

Ocular inflammation is one of the most common comorbidities associated to ophthalmic surgeries and disorders. Since conventional topical ophthalmic treatments present disadvantages such as low bioavailability and relevant side effects, natural alternatives constitute an unmet medical need. In this sense, lactoferrin, a high molecular weight protein, is a promising alternative against inflammation. However, lactoferrin aqueous instability and high nasolacrimal duct drainage compromises its potential effectiveness. Moreover, nanotechnology has led to an improvement in the administration of active compounds with compromised biopharmaceutical profiles. Here, we incorporate lactoferrin into biodegradable polymeric nanoparticles and optimized the formulation using the design of experiments approach. A monodisperse nanoparticles population was obtained with an average size around 130 nm and positive surface charge. Pharmacokinetic and pharmacodynamic behaviour were improved by the nanoparticles showing a prolonged lactoferrin release profile. Lactoferrin nanoparticles were non-cytotoxic and non-irritant neither in vitro nor in vivo. Moreover, nanoparticles exhibited significantly increased anti-inflammatory efficacy in cell culture and preclinical assays. In conclusion, lactoferrin loaded nanoparticles constitute a safe and novel nanotechnological tool suitable for the treatment of ocular inflammation.

Topics: Administration, Ophthalmic; Animals; Anterior Eye Segment; Biological Availability; Eye Diseases; Humans; Inflammation; Lactoferrin; Nanoparticles; Ophthalmic Solutions; Particle Size; Rabbits

Lactoferrin is a glycoprotein found at high concentrations within exocrine secretions, including tears. Low levels of lactoferrin have been implicated in the loss of tear secretion and ageing. Furthermore, lactoferrin possesses a range of functionalities, including anti-inflammatory properties and the ability to modulate the gut microbiota. Expanding evidence demonstrates a crucial role of the gut microbiota in immune regulation and development. The specific composition of bacterial species of the gut has a profound influence on local and systemic inflammation, leading to a protective capacity against a number of inflammatory diseases, potentially by the induction of regulatory immune cells. In this study, we demonstrated that oral administration of lactoferrin maintains tear secretion in a restraint and desiccating stress induced mouse model of dry eye disease. Furthermore, we revealed that lactoferrin induces the reduction of inflammatory cytokines, modulates gut microbiota, and induces short-chain fatty acid production. Whereas, the antibiotic vancomycin abrogates the effects of lactoferrin on dry eye disease and significantly reduces short-chain fatty acid concentrations. Therefore, this protective effect of LF against a mice model of DED may be explained by our observations of an altered gut microbiota and an enhanced production of immunomodulatory short-chain fatty acids.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Cytokines; Disease Models, Animal; DNA, Bacterial; Dry Eye Syndromes; Fatty Acids, Volatile; Female; Gastrointestinal Microbiome; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Protective Agents; Signal Transduction; Tears; Treatment Outcome; Vancomycin

Primary infection with

Topics: Animals; Cord Factors; Female; Fluoroquinolones; Granuloma; Humans; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Mycobacterium; Recombinant Proteins

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cattle; Colonic Neoplasms; Crohn Disease; Disease Models, Animal; Inflammation; Lactoferrin; Male; Mice; Mice, Inbred C57BL

Fecal lactoferrin (FL) levels may mirror drug-induced changes in inflammation in ulcerative colitis and Crohn disease in a timely way and could be used to assess loss of response (LOR) to biologics.. This study is a retrospective outcome review in 61 patients on adalimumab, infliximab, or vedolizumab managed in our center and followed for 6 to 24 months. Patients were 1) in clinical remission or 2) were experiencing possible LOR.. For group 1, in 71% of 31 patients, FL slowly increased during the therapeutic interval (R2 = 0.769; P < 0.001), thus reflecting increasing inflammation as drug concentrations decreased. In the remaining patients, FL was undetectable throughout the therapeutic interval because of a stronger suppression of inflammation. For group 2, in 30 patients negative for infections, FL levels measured 1 to 3 days after infusion/injection compared to preadministration values either increased (nonresponders)-in these patients the medication was switched to another class; partially decreased (partial responders)-the therapeutic interval was shortened; or were normal throughout (responders)-causes for symptoms unrelated to disease activity were found for all. After FL-based management, 3-month standardized clinical scores were normalized in both partial responders (0.58 ± 0.21 vs 0.13 ± 0.09; P < 0.001) and nonresponders (0.81 ± 0.17 vs 0.12 ± 0.08; P < 0.001), and FL levels dropped by up to 99%.. Levels of FL reflect drug-induced changes in mucosal inflammation in a timely way, thus enabling rapid assessment of therapeutic response in patients with ulcerative colitis and with Crohn disease. In patients with suspected LOR, FL levels before and after infusion/injection accurately separated responders, partial responders, and nonresponders. The strategy proposed here is simple, accurate, and easily applicable to clinical practice.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Inflammation; Infliximab; Lactoferrin; Retrospective Studies

Contemporary studies have discredited the methods used to exclude urinary tract infection (UTI) when treating overactive bladder (OAB). Thus we must revisit the OAB phenotype to check that UTI has not been overlooked.. To examine the differences in urinary cytokines IL6 and lactoferrin in OAB patients compared to controls, with references to microscopy of urine and enhanced quantitative urine culture.. A blinded, prospective cohort study with normal controls using six repeated measures, achieved two-monthly, over 12 months.. The differences between patients and controls in urine IL6 (F = 49.0, p < .001) and lactoferrin (F = 228.5, p < .001) were significant and of a magnitude to have clinical implications. These differences were for lactoferrin correlated to symptoms (9.3, p = .003); for both to pyuria (IL6 F = 66.2, p < .001, Lactoferrin F = 73.9, p < .001); and for IL6 microbial abundance (F = 5.1, p = .024). The pathological markers had been missed by urinary dipsticks and routine MSU culture.. The OAB phenotype may encompass patients with UTI that is being overlooked because of the failure of standard screening methods.

Topics: Aged; Female; Humans; Inflammation; Interleukin-6; Lactoferrin; Middle Aged; Prospective Studies; Single-Blind Method; Urinary Bladder, Overactive

Macrophage activation and osteoclastogenesis are hallmarks of inflammatory osteolysis and may be targeted by the local application of liquid platelet-rich fibrin (PRF). Liquid PRF is produced by a hard spin of blood in the absence of clot activators and anticoagulants, thereby generating an upper platelet-poor plasma (PPP) layer, a cell-rich buffy coat layer (BC; termed concentrated-PRF or C-PRF), and the remaining red clot (RC) layer. Heating PPP has been shown to generate an albumin gel (Alb-gel) that when mixed back with C-PRF generates Alb-PRF having extended working properties when implanted

Topics: Animals; Imiquimod; Inflammation; Inflammation Mediators; Lactoferrin; Lipopolysaccharides; Macrophage Activation; Macrophages; Membrane Glycoproteins; Mice; Osteoclasts; Osteogenesis; Phenotype; Platelet-Rich Plasma; Poly I-C; RAW 264.7 Cells; Toll-Like Receptor 3; Toll-Like Receptor 7

Lactoferrin (Lf) is a conserved iron-binding glycoprotein with antimicrobial activity, which is present in secretions that recover mucosal sites regarded as portals of invaded pathogens. Although numerous studies have focused on exogenous Lf, little is known about its expression of endogenous Lf upon bacterial infection. In this study, we investigated the distribution of Lf in mice intestine during

Topics: Animals; Bacterial Infections; Disease Models, Animal; Escherichia coli; Inflammation; Intestines; Lactoferrin; Male; Mice, Inbred C57BL; Neutrophils

Guided bone regeneration refers to the process in which bone defects could be regenerated by facilitated healing through the use of membranes, potentially with the delivery of osteoinductive molecules, however, the regeneration often failed due to inflammation during bone formation. In this study, we developed a membrane immobilized with lactoferrin to modulate both bone regeneration and inflammatory responses. Lactoferrin was immobilized on electrospun nanofibers (LF50) by exploiting an adhesive polydopamine coating method. When human adipose-derived stem cells (hADSCs) were seeded onto the nanofibers, the LF50 significantly increased the osteogenic differentiation. For example, the gene expression of osteopontin was 6.9 ± 2.3 times greater in the cells on LF50 than the cells on unmodified nanofibers without lactoferrin. In addition, the gene expression of tumor necrosis factor-alpha (

Topics: Animals; Bone Regeneration; Cell Differentiation; Guided Tissue Regeneration; Inflammation; Lactoferrin; Mice; Nanofibers; Osteogenesis; RAW 264.7 Cells; Tissue Scaffolds

Alzheimer's disease (AD) is neurological disorder characterized by dementia which causes severe problems with behavior, thinking and memory. Systemic administration of therapeutics to the central nervous system (CNS) is usually associated with very low efficiency due to presence of blood brain barrier (BBB), which only allows permeation of few types of molecules from the circulation to the CNS. As an alternative, naturally amphiphilic micelles can be utilized to enhance targeted drug delivery to the brain. In this sense, lactoferrin (LF) was covalently attached to conjugated linoleic acid (CLA) via carbodiimide coupling reaction to form a new micellar nanoplatform with particle size of about 53 nm. Afterwards, fabricated micelles were further loaded once again with CLA to enhance its delivery to the CNS. In vitro drug release study revealed that CLA exhibited sustained release at pH 6.8, associated with good hemocompatibility without any remarkable in vivo toxicity in terms of liver and kidney functions. Moreover, in vivo studies showed that the fabricated micelles manifested enhanced in vivo biodistrbution in brain tissue due to the active targeting potential of LF. Additionally, drug-loaded LF-CLA micelles exhibited enhanced cognitive capabilities, reduced brain oxidative stress, inflammation, apoptosis and acetylcholine esterase activity, besides a decline in the deposition of amyloid β peptide1-42 in aluminum chloride Alzheimer's-induced animal model. CLA-based micelles could be a promising CNS actively targeted delivery system with a sophisticated potential to reduce AD symptoms.

Topics: Acetylcholinesterase; Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Behavior Rating Scale; Blood-Brain Barrier; Disease Models, Animal; Drug Carriers; Drug Liberation; Hydrogen-Ion Concentration; Inflammation; Kidney; Lactoferrin; Linoleic Acids, Conjugated; Liver; Male; Memory; Micelles; Microscopy, Electron, Transmission; Nanostructures; Oxidative Stress; Particle Size; Rats; Rats, Wistar; Spectroscopy, Fourier Transform Infrared

The neutrophil granule protein lactoferrin is cleaved and accumulates in efferocytic macrophages as inflammation is resolved. Two peptides present within a resolution-associated 17 kDa fragment of lactoferrin promote the termination of inflammation in vivo by enhancing murine macrophage reprogramming. Here, we report that these two bioactive tripeptides, phenylalanine-lysine-aspartic acid and phenylalanine-lysine-glutamic acid (FKD and FKE, respectively), inhibit ERK and cJun activation following human macrophage exposure to LPS. In addition, these peptides at low concentrations (1-10 μM) modulate human macrophage reprogramming to an anti-inflammatory/pro-resolving phenotype. This was reflected by inhibition of LPS-induced TNF-α and IL-6 secretion and increased IL-10 levels. Moreover, we found naturally occurring FKE analogs (FKECH and FKECHLA) can recapitulate the activity of the short peptide in regulating macrophage cytokine secretion, whereas a reversed EKF peptide was inert in this respect. Curiously, FKD and FKE also regulated cytokine production by bone marrow-derived mouse macrophages, but in a very different fashion than their effect on human macrophages. Thus, lactoferrin peptides limit pro-inflammatory signaling and cytokine production by LPS-activated human macrophages and thereby enhance the resolution of inflammation.

Topics: Animals; Cell Line; Cytokines; Extracellular Signal-Regulated MAP Kinases; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lactoferrin; Lipopolysaccharides; Macrophage Activation; Macrophages; MAP Kinase Signaling System; Mice; p38 Mitogen-Activated Protein Kinases; Peptides; Tumor Necrosis Factor-alpha

Our previous study showed that intrauterine-infused lipopolysaccharide (LPS) can be translocated to the mammary gland to induce weak inflammation. This study aimed to determine whether dexamethasone treatment facilitated the translocation of LPS from the uterus to the mammary gland to induce a heavy inflammatory response. Sixteen goats were divided into control and LPS groups, subjected to daily dexamethasone administration before saline or LPS infusion. Milk and blood samples were collected before and after LPS infusion to determine the milk yield and somatic cell count (SCC) and blood leucocyte count (BLC), cytokines, antimicrobial peptides and serum amyloid A (SAA) concentrations. Mammary gland tissues were collected from two goats before and 24 hr after LPS infusion for immunohistochemical analysis of LPS. The mean SCC in the LPS group was significantly higher, whereas the milk yield was significantly lower than that in the control group after LPS infusion. The mean BLC in the LPS group was significantly lower than in the control group after LPS infusion. Furthermore, milk concentrations of IL-1β, S100A8 and lactoferrin were higher in the LPS group than in the control group after infusion. LPS was detected in the connective tissues and inner alveolar spaces of the mammary glands 24 hr after LPS infusion. We concluded that dexamethasone administration facilitated the translocation of intrauterine-infused LPS to the mammary gland, where it induced an inflammatory response. Therefore, LPS translocated from other organs, such as the uterus, can induce heavy inflammation in the mammary gland under immunosuppressive conditions.

Topics: Animals; Calgranulin A; Dexamethasone; Female; Goats; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Lactation; Lactoferrin; Leukocyte Count; Lipopolysaccharides; Mammary Glands, Animal; Milk; Uterus

Lactoferrin (LF) plays critical roles in various physiological processes. However, its protective effects on small intestinal epithelial cells remain poorly understood. This study aimed to investigate its protective effects and underlying mechanisms in vitro on lipopolysaccharide (LPS)-challenged intestinal porcine epithelial cells (IPEC-J2 cells). The IPEC-J2 cells were treated with or without LPS and LF for 24 h and analyzed using various assays. The results indicated that the LPS treatment induced the secretion of pro-inflammatory cytokines [interleukin (IL)-1β, IL-8, and TNF-α], increased cell permeability, and enhanced reactive oxygen species (ROS) production. The LF treatment decreased the secretion and gene expression of IL-1β and downregulated the phosphorylation levels of NF-κB, IκB, P38, and ERK1/2 in LPS-challenged cells. Moreover, the LF treatment decreased cell permeability, enhanced the expression of claudin-1 protein, and inhibited the expression of the myosin light-chain kinase (MLCK) protein in LPS-challenged cells. It also reduced the ROS and MDA production as well as upregulated the GSH-Px activity and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Taken together, these results suggested that LF alleviated the LPS-induced cellular inflammation through the attenuation of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (MAPK) pathways, maintaining cellular barrier integrity and mitigating oxidative stress.

Topics: Animals; Cell Line; Cytokines; Enterocytes; I-kappa B Proteins; Inflammation; Interleukin-1beta; Lactoferrin; Lipopolysaccharides; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Permeability; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Swine

Lactoferrin (LF) is a monomer glycoprotein in the mammalian colostrum that has multiple biological activities and a high affinity for iron ions. Not only does it have strong antibacterial activity, it also can regulate the release of cytokines in inflammatory areas, activate immune cells, and inhibit inflammatory diseases caused by non-pathogenic bacteria and the development of tumors. However, the anti-inflammatory mechanism of LF in inflammatory skin diseases induced by Propionibacterium acnes (P. acnes) has not been elucidated in vitro and in vivo. In this study, we investigated the effects of LF on the generation of inflammatory cytokines in HaCaT cells induced by heat-killed P. acnes. The expression of pro-inflammatory cytokines IL-8 increased after induction of HaCaT by heat-killed P. acnes, but it decreased significantly after LF treatment. Western blotting was used to examine the levels of TLR2, nuclear factor (NF) κB and intercellular cell adhesion molecule 1 protein induced by P. acnes in HaCaT cells, and the results showed that the levels were inhibited by LF. In addition, activated P. acnes (1 × 107 CFU/mL) was injected into the ears of experimental mice, which induced inflammation 24 hours after the injection. However, immunohistochemical analysis showed a significant reduction in the inflammatory response after LF treatment in the right ear relative to the untreated left ear, and the same result was seen with western blotting. In summary, this study revealed the treatment effect of LF on P. acnes-induced inflammation, thus providing support for the anti-acne properties of LF.

Topics: Acne Vulgaris; Animals; Anti-Inflammatory Agents; Inflammation; Lactoferrin; Mice; Propionibacterium acnes

Inflammation plays a critical role in the development of severe neonatal morbidities. Myeloid-derived suppressor cells (MDSCs) were recently implicated in the regulation of immune responses in newborns. Here, we report that the presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum. Low amounts of MDSCs at birth predicted the development of severe pathology in preterm infants - necrotizing enterocolitis (NEC). In vitro treatment of newborn neutrophils and monocytes with LF converted these cells to MDSCs via the LRP2 receptor and activation of the NF-κB transcription factor. Decrease in the expression of LRP2 was responsible for the loss of sensitivity of adult myeloid cells to LF. LF-induced MDSCs (LF-MDSCs) were effective in the treatment of newborn mice with NEC, acting by blocking inflammation, resulting in increased survival. LF-MDSCs were more effective than treatment with LF protein alone. In addition to affecting NEC, LF-MDSCs demonstrated potent ability to control ovalbumin-induced (OVA-induced) lung inflammation, dextran sulfate sodium-induced (DSS-induced) colitis, and concanavalin A-induced (ConA-induced) hepatitis. These results suggest that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.

Topics: Adult; Animals; Animals, Newborn; Cell- and Tissue-Based Therapy; Disease Models, Animal; Enterocolitis, Necrotizing; Female; Humans; In Vitro Techniques; Infant, Newborn; Infant, Premature; Inflammation; Lactoferrin; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Derived Suppressor Cells; NF-kappa B

Objective- Increasing evidence shows that resveratrol has antiatherogenic effects, but its underlying mechanisms are unknown. Thus, we evaluated the molecular mechanisms underlying the antiatherogenic effect of resveratrol. Approach and Results- Using the previously established mouse atherosclerosis model of partial ligation of the left carotid artery, we evaluated the role of resveratrol in antiatherosclerosis. We attempted to determine the mechanisms associated with focal adhesions using vascular endothelial cells. The results showed that resveratrol stimulated focal adhesion kinase cleavage via resveratrol-increased expression of lactoferrin in endothelial cells. Furthermore, we found that an N-terminal focal adhesion kinase fragment cleaved by resveratrol contained the FERM (band 4.1, ezrin, radixin, and moesin)-kinase domain. Furthermore, resveratrol inhibited lipopolysaccharide-stimulated adhesion of THP-1 human monocytes by decreased expression of ICAM-1 (intercellular adhesion molecule-1). A decreased ICAM-1 level was also observed in the left carotid artery of mice treated with resveratrol. To understand the relationship between resveratrol-induced antiinflammation and focal adhesion disruption, endothelial cells were transfected with FERM-kinase. Ectopically expressed FERM-kinase, the resveratrol-cleaved focal adhesion kinase fragment, was found in the nuclear fraction and inhibited the transcription level of icam-1 via the Nrf2 (nuclear factor erythroid 2-related factor 2)-antioxidant response element complex. Finally, ectopically expressed FERM-kinase blocked tumor necrosis factor-α- or IL- (interleukin) stimulated monocytic binding to endothelial cells. Conclusions- Our results show that resveratrol inhibits the expression of ICAM-1 via transcriptional regulation of the FERM-kinase and Nrf2 interaction, thereby blocking monocyte adhesion. These suppressive effects on the inflammatory mechanism suggest that resveratrol delayed the onset of atherosclerosis.

Topics: Active Transport, Cell Nucleus; Animals; Atherosclerosis; Carotid Arteries; Carotid Stenosis; Cell Adhesion; Disease Models, Animal; Down-Regulation; Endothelium, Vascular; Enzyme Induction; Focal Adhesion Kinase 1; Inflammation; Lactoferrin; Ligation; Mice; Mice, Knockout, ApoE; Monocytes; NF-E2-Related Factor 2; Random Allocation; Resveratrol; Transcription, Genetic

To investigate whether C-reactive protein (CRP, a general marker of inflammation), neopterin (activated macrophages), lactoferrin (activated neutrophils), and endothelial function (flow-mediated vasodilation [FMD]) are associated with cardiorespiratory fitness (peak oxygen uptake [VO. This was a cross-sectional association study based on the population-based HUNT3 Fitness Study performed from May 15, 2007, through June 23, 2008. Seven hundred forty self-reported healthy respondents (327 women) identified as having the MetSyn were age- and sex-matched with 692 controls (307 women) from the same cohort. Associations between the inflammatory biomarkers and VO. The CRP level was negatively associated with VO. The CRP level was strongly associated with VO

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Cardiorespiratory Fitness; Case-Control Studies; Cohort Studies; Cross-Sectional Studies; Female; Humans; Inflammation; Lactoferrin; Male; Metabolic Syndrome; Middle Aged; Neopterin; Oxygen Consumption; Sex Distribution

Although C5a receptor (C5aR) interacting with its agonist C5a promotes acute inflammation during the initiation phase, the roles of the recycling C5aR during the resolution phase are still unclear. We found that C5aR interacted with its antagonist/agonist ribosomal protein S19 (RP S19) polymer or a RP S19 polymer functional analogue S-tagged C5a/RP S19, which connects an RP S19 C-terminus (IAGQVAAANKKH) to the S-tagged C5a C-terminus, promoted acute inflammation at the resolution phase via an activation of the apoptosis-inducing transcription factor delta lactoferrin (δLf) in neutrophils and the membrane mobilizing factor full-length annexin A3 (ANXA3) in macrophages. To confirm the antagonistic system of the recycling C5aR, S-tagged δLf-coupled BrCN-activated Sepharose 4B beads were incubated with cytoplasmic proteins and identified a neutrophil-specific δANXA3 via pull-down experiments. The S-tagged C5a/RP S19-induced agonistic functions in macrophage-like cells that were differentiated from human promyelocytic leukemia HL-60 cells by phorbol-12-myristate-13-acetate were suppressed by δLf and δANXA3 co-overexpression. δANXA3 seems to participate in the antagonistic system of the neutrophil C5aR involving IAGQVAAANKKH and δLf. Most likely, δANXA3 works as antagonist for the recycling C5aR on neutrophils during the resolution phase of acute inflammation.

Topics: Annexin A3; Apoptosis; Complement C5a; Humans; Inflammation; Lactoferrin; Macrophages; Neutrophils; Receptor, Anaphylatoxin C5a; Ribosomal Proteins

Myeloid-derived suppressor cells (MDSCs) are pathologically activated and relatively immature myeloid cells that have been implicated in the immunological regulation of many pathologic conditions. Phenotypically and morphologically, MDSCs are similar to neutrophils (PMN-MDSCs) and monocytes (M-MDSCs). However, they have potent suppressive activity and distinct gene expression profiles and biochemical characteristics. No or very few MDSCs are observed in steady-state physiological conditions. Therefore, until recently, accumulation of MDSCs was considered a consequence of pathological processes or pregnancy. Here, we report that MDSCs with a potent ability to suppress T cells are present during the first weeks of life in mice and humans. MDSC suppressive activity was triggered by lactoferrin and mediated by nitric oxide, PGE2, and S100A9 and S100A8 proteins. MDSCs from newborns had a transcriptome similar to that of tumor MDSCs, but with strong upregulation of an antimicrobial gene network, and had potent antibacterial activity. MDSCs played a critical role in control of experimental necrotizing enterocolitis (NEC) in newborn mice. MDSCs in infants with very low weight, who are prone to NEC, had lower MDSC levels and suppressive activity than did infants with normal weight. Thus, the transitory presence of MDSCs may be critical for regulation of inflammation in newborns.

Topics: Animals; Animals, Newborn; Calgranulin A; Calgranulin B; Dinoprostone; Enterocolitis, Necrotizing; Gene Expression Regulation; Humans; Infant, Very Low Birth Weight; Inflammation; Lactoferrin; Mice; Myeloid-Derived Suppressor Cells; Nitric Oxide

Bioactive components of human milk, such as human lactoferrin (hLF), play an essential role in gut microbiome homeostasis and protection against neonatal inflammatory diseases. Neonatal intestinal macrophages display a proinflammatory profile that might contribute to inflammatory mucosal injury. Therefore, the aim of the study was to investigate the immunomodulatory effects of hLF on differentiation and activation of monocyte-derived macrophages (moMϕ). Monocytes isolated from umbilical cord blood of term neonates and peripheral blood of healthy adults were differentiated in the absence or presence of hLF, and differentiation, apoptosis and phagocytosis were evaluated. Cytokine production, Toll-like receptor (TLR) signalling and activation marker expression were investigated upon activation with lipopolysaccharide (LPS) and lipoteichoic acid (LTA) challenge. We demonstrate that hLF-differentiated moMϕ exhibit decreased TLR-4 expression, TLR signalling, proinflammatory cytokine secretion and intracellular tumour necrosis factor (TNF)-α production. Investigation of differentiation markers, morphology and induction of apoptosis showed no alteration in lactoferrin-differentiated moMϕ. Taken together, hLF promote anergic/anti-inflammatory effects by TLR expression and pathway interference, resulting in a diminished proinflammatory moMϕ phenotype. The anergic/anti-inflammatory properties of hLF might contribute to the prevention of harmful TLR-mediated inflammatory disorders in the developing gut of premature infants.

Topics: Apoptosis; Cell Differentiation; Cells, Cultured; Cytokines; Fetal Blood; Gastrointestinal Tract; Humans; Infant, Newborn; Inflammation; Lactoferrin; Lipopolysaccharides; Macrophages; Milk, Human; Monocytes; Phagocytosis; Signal Transduction; Teichoic Acids; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Neutrophils represent the most abundant immune cells recruited to inflamed tissues. A lack of dedicated tools has hampered their detection and study. We show that a synthesized peptide, MUB

Topics: Adult; Animals; Biomarkers; Carbocyanines; Dysentery, Bacillary; Female; Fluorescent Dyes; Guinea Pigs; Humans; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; Peptides; Rabbits; Shigella

The inherent disease susceptibility of veal calves results in frequent antimicrobial use. Improvements in antimicrobial stewardship necessitate alternative therapies to improve calf health and growth, while reducing the need for antimicrobials important to human health. This study investigated the effect of 2 alternative therapies, lactoferrin (an iron-binding protein found in colostrum) and cinnamaldehyde (an essential oil of the cinnamon plant) on growth, disease incidence, and mortality risk in special-fed veal calves. On the day of arrival to the growing facility (3 to 7 d of age), calves (n = 80 per treatment) were randomized to 1 of 3 treatments: (1) control (no supplement), (2) lactoferrin (1 g/d in milk replacer for 7 d), or (3) cinnamaldehyde (1 g/d in milk replacer for 21 d). Body weight was measured on the day of arrival (d 0), 21, and 42 d postarrival. Health assessments were performed twice weekly through 21 d, and mortality records were obtained through 6 wk postarrival. A repeated-measures ANOVA was used to compare growth between treatment groups, and a Poisson regression model (PROC GENMOD, SAS v. 9.4, SAS Institute Inc., Cary, NC) was used to test differences between groups in the incidence of diarrhea (fecal score ≥2 with and without depression and temperature) and disease through 3 wk postarrival. Body weight and average daily gain were similar between treatments. Neither lactoferrin nor cinnamaldehyde had an effect on diarrhea incidence. However, the risk of navel inflammation was significantly lower for calves that received cinnamaldehyde compared with calves in the control group. Mortality through 6 wk postarrival was low, with 4, 1, and 0 deaths from the control, lactoferrin, and cinnamaldehyde treatment groups, respectively. Additional research is needed to investigate various doses of these alternative therapies on calf health and growth, in addition to different routes of administration.

Topics: Acrolein; Animal Feed; Animals; Anti-Bacterial Agents; Body Weight; Cattle; Cattle Diseases; Colostrum; Diarrhea; Diet; Dietary Supplements; Female; Health Status; Inflammation; Lactoferrin; Milk; Weight Gain

During the resolution of inflammation, macrophages engulf apoptotic polymorphonuclear cells (PMN) and can accumulate large numbers of their corpses. Here, we report that resolution phase macrophages acquire the neutrophil-derived glycoprotein lactoferrin (Lf) and fragments thereof

Topics: Animals; Apoptosis; Cattle; Cells, Cultured; Cytokines; Disease Models, Animal; Extracellular Traps; Female; Humans; Inflammation; Lactoferrin; Macrophages; Male; Mastitis, Bovine; Mice; Mice, Inbred C57BL; Neutrophils; Peptide Fragments; Peritonitis; Phagocytosis

Streptococcus pneumoniae (pneumococcus), the major pathogen for pneumonia, commonly colonizes the lung, but the mechanism underlying the coordination of virulence factors during invasion via the host protein remains poorly understood. Bacterial lysis releases the components of the cell wall, and triggers innate immunity and the subsequent secretion of pro-inflammatory cytokines. Previously, the virulence of the pep27 mutant was shown to be attenuated as a feasible candidate for vaccine development. However, the role of pep27 gene, belonging to the vancomycin-resistance locus (vncRS operon), in virulence, is largely unknown. This study demonstrates that transferrin in the host serum reduces the survival of the host during S. pneumoniae infections in mice. The exposure of the pneumococcal D39 strain to lactoferrin induced the vncRS operon, lysis, and subsequent in vivo cytokine production, resulting in lung inflammation. However, these responses were significantly attenuated in pneumococci harboring a mutation in pep27. Mechanistically, the VncS ligand, identified as lactoferrin, induced the vncRS operon and increased the in vivo mortality rates. Thus, serum-induced activation of vncRS plays an essential role in inducing pneumonia.

Topics: A549 Cells; Animals; Bacterial Proteins; Cytokines; Humans; Immunity, Innate; Inflammation; Lactoferrin; Lung; Male; Mice, Nude; Mutation; Operon; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Transferrin; Vancomycin; Virulence

Neutrophil extracellular traps (NETs) are extracellular DNA filaments formed during neutrophil activation. This process, called netosis, was originally associated with neutrophil antibacterial properties. However, several lines of evidence now suggest a major role for netosis in thrombosis, autoimmune diseases, and cancer. We demonstrate here that highly purified human blood monocytes are also capable of extracellular trap (ET) release in response to several stimuli. Monocyte ETs display a morphology analogous to NETs and are associated with myeloperoxidase (MPO), lactoferrin (LF), citrullinated histones, and elastase. Monocyte ET release depends on oxidative burst but not on MPO activity, in contrast to neutrophils. Moreover, we demonstrate procoagulant activity for monocyte ETs, a feature that could be relevant to monocyte thrombogenic properties. This new cellular mechanism is likely to have implications in the multiple pathologic contexts where monocytes are implicated, such as inflammatory disorders, infection, or thrombosis.

Topics: Extracellular Traps; Histones; Humans; Infections; Inflammation; Lactoferrin; Monocytes; Pancreatic Elastase; Peroxidase; Thrombosis

The iron-binding glycoprotein lactoferrin (LF) is naturally present in human breast milk. Several studies suggest that LF contributes to infant health and development owing to a variety of protective effects, including antimicrobial and anti-inflammatory features. Therefore, we aimed to elucidate its protective properties on intestinal epithelial barrier dysfunction induced by infection or inflammation using the human epithelial cell culture models HT-29/B6 and T84. During barrier perturbation induced by the proinflammatory cytokine tumor necrosis factor α (TNF-α), bovine LF restored tight junction (TJ) morphometry and inhibited TNF-α-induced epithelial apoptosis. This resulted in an attenuation of the TNF-α-induced decrease in transepithelial resistance (TER) and increases in permeability of fluorescein and FITC-dextran (4 kDa) and was as effective as the apoptosis inhibitor Q-VD-Oph. The enteropathogenic bacterium Yersinia enterocolitica is a frequent cause of diarrhea in early childhood. This involves focal changes in TJ protein expression and localization. LF diminished the Y. enterocolitica-induced drop in TER in the present in vitro model, which was paralleled by an inhibition of the Yersinia-induced reduction of claudin-8 expression via c-Jun kinase signaling. In conclusion, LF exerts protective effects against inflammation- or infection-induced barrier dysfunction in human intestinal cell lines, supporting its relevance for healthy infant development.

Topics: Anti-Inflammatory Agents; Apoptosis; Cell Line; Humans; Inflammation; Intestinal Mucosa; Lactoferrin; Tight Junctions; Tumor Necrosis Factor-alpha; Yersinia enterocolitica

Lactoferrin (LTF), an important first line defense molecule against infection, is a common target for humoral autoimmune reactions in humans. Since LTF is a multifunctional protein capable of activating innate immune cells via various surface receptors, we hypothesized that LTF-containing immune complexes (ICs) (LTF-ICs), likely formed in patients with high titer anti-LTF autoantibodies, could possess unique monocyte/macrophage-activating properties compared with other ICs. ELISA analysis on serum samples from rheumatoid arthritis (RA) patients (n = 80) and healthy controls (n = 35) for anti-LTF autoantibodies confirmed a positive correlation between circulating LTF-specific IgG and RA. ICs between human LTF and LTF-specific IgG purified from patient sera or immunized rabbits and mice, but not control ICs, LTF or Abs alone, elicited strong production of TNF-α and IL-1β by freshly fractionated human peripheral blood monocytes and monocytes-derived macrophages. Furthermore, LTF-ICs utilized both membrane-anchored CD14 and CD32a (FcγRIIa) to trigger monocyte activation in an internalization-, Toll-like receptor (TLR)4- and TLR9-dependent manner, and also that LTF-IC-induced cytokine production was blocked by specific inhibitors of caspase-1, NF-κB and MAPK. These results uncover a possible pathway for LTF-ICs perpetuating local inflammation and contributing to the pathogenesis of autoimmune diseases by triggering activation of infiltrating monocytes or tissue macrophages in vivo.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Anti-Idiotypic; Antigen-Antibody Complex; Arthritis, Rheumatoid; Autoantibodies; Autoimmunity; Female; Humans; Immunity, Humoral; Immunoglobulin G; Infections; Inflammation; Lactoferrin; Macrophages; Male; Middle Aged; Monocytes; Tumor Necrosis Factor-alpha

To investigate the anti-adhesive mechanisms of PXL01 in sodium hyaluronate (HA) by using the rabbit lactoferrin peptide, rabPXL01 in HA, in a rabbit model of healing tendons and tendon sheaths. The mechanism of action for PXL01 in HA is interesting since a recent clinical study of the human lactoferrin peptide PXL01 in HA administered around repaired tendons in the hand showed improved digit mobility.. On days 1, 3, and 6 after tendon injury and surgical repair, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to assess mRNA expression levels for genes encoding the mucinous glycoprotein PRG4 (also called lubricin) and a subset of matrix proteins, cytokines, and growth factors involved in flexor tendon repair. RabPXL01 in HA was administered locally around the repaired tendons, and mRNA expression was compared with untreated repaired tendons and tendon sheaths.. We observed, at all time points, increased expression of PRG4 mRNA in tendons treated with rabPXL01 in HA, but not in tendon sheaths. In addition, treatment with rabPXL01 in HA led to repression of the mRNA levels for the pro-inflammatory mediators interleukin (IL)-1β, IL-6, and IL-8 in tendon sheaths.. RabPXL01 in HA increased lubricin mRNA production while diminishing mRNA levels of inflammatory mediators, which in turn reduced the gliding resistance and inhibited the adhesion formation after flexor tendon repair.

Topics: Actins; Animals; Collagen; Female; Gene Expression Regulation; Humans; Hyaluronic Acid; Inflammation; Lactoferrin; Muscle, Smooth; Myofibroblasts; Proteoglycans; Rabbits; Tendon Injuries; Tendons; Tissue Adhesions; Wound Healing

Chlamydia trachomatis is an obligate, intracellular pathogen responsible for the most common sexually transmitted bacterial disease worldwide, causing acute and chronic infections. The acute infection is susceptible to antibiotics, whereas the chronic one needs prolonged therapies, thus increasing the risk of developing antibiotic resistance. Novel alternative therapies are needed. The intracellular development of C. trachomatis requires essential nutrients, including iron. Iron-chelating drugs inhibit C. trachomatis developmental cycle. Lactoferrin (Lf), a pleiotropic iron binding glycoprotein, could be a promising candidate against C. trachomatis infection. Similarly to the efficacy against other intracellular pathogens, bovine Lf (bLf) could both interfere with C. trachomatis entry into epithelial cells and exert an anti-inflammatory activity. In vitro and in vivo effects of bLf against C. trachomatis infectious and inflammatory process has been investigated. BLf inhibits C. trachomatis entry into host cells when incubated with cell monolayers before or at the moment of the infection and down-regulates IL-6/IL-8 synthesized by infected cells. Six out of 7 pregnant women asymptomatically infected by C. trachomatis, after 30 days of bLf intravaginal administration, were negative for C. trachomatis and showed a decrease of cervical IL-6 levels. This is the first time that the bLf protective effect against C. trachomatis infection has been demonstrated.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Cattle; Chlamydia Infections; Chlamydia trachomatis; Clinical Trials as Topic; Female; HeLa Cells; Humans; Inflammation; Lactoferrin; Pregnancy

Lactoferrin (Lf), an iron-chelating glycoprotein of innate immunity, produced by exocrine glands and neutrophils in infection/inflammation sites, is one of the most abundant defence molecules in airway secretions. Lf, a pleiotropic molecule, exhibits antibacterial and anti-inflammatory functions. These properties may play a relevant role in airway infections characterized by exaggerated inflammatory response, as in Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) subjects. To verify the Lf role in Pseudomonas aeruginosa lung infection, we evaluated the efficacy of aerosolized bovine Lf (bLf) in mouse models of P. aeruginosa acute and chronic lung infections. C57BL/6NCrl mice were challenged with 10

Topics: Administration, Inhalation; Aerosols; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cattle; Cytokines; Disease Models, Animal; Inflammation; Inflammation Mediators; Lactoferrin; Lung Diseases; Male; Mice; Mice, Inbred C57BL; Neutrophils; Pseudomonas aeruginosa; Pseudomonas Infections

The short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is an important innate material in the upper airway, and lactoferrin (LF) aids the innate functions in humans. In this study, a nasal epithelial model was used to investigate how LF modulates SPLUNC1 to reduce the inflammatory process mediated by lipopolysaccharide (LPS). The inflammation of human RPMI-2650 cells was induced with LPS to evaluate SPLUNC1 expression after treating the cells with bovine LF (bLF). The interaction pathway between LF and SPLUNC1 in LPS-induced inflammation was further investigated. Our study reveals that the addition of bLF results in the recovery of SPLUNC1 expression in nasal epithelial cells under LPS-induced inflammation. MAPK is involved in the main pathway for the SPLUNC1 and bLF interaction. Decreased SPLUNC1 function could be recovered by addition of bLF. The MEK1/2-MAPK signaling pathway is crucial for the SPLUNC1 and bLF interaction. Therefore, LF could support SPLUNC1 in the innate immunity recovery process.

Topics: Animals; Cattle; Cells, Cultured; Epithelial Cells; Glycoproteins; Humans; Inflammation; Lactoferrin; Lipopolysaccharides; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mitogen-Activated Protein Kinases; Nasal Mucosa; Phosphoproteins; Signal Transduction

Bovine lactoferrin (bLf) up-modulates intestinal IgA that is essential for homeostasis and which might confer protection to the distal small intestine that is vulnerable to inflammation. This study analyzed the effects of bLf administered orally on the IgA response at inductive (Peyer's patches) and effector (lamina propria) sites of the distal small intestine in mice. Groups of five healthy male BALB/c mice were orally treated with 5 mg of bLf for 7, 14, 21, or 28 days. Then, mice were killed and the distal small intestine was dissected. Intestinal fluid samples were analyzed to determine IgA and IgM levels by enzyme-immuno assay. Peyer's patches and lamina propria were analyzed for IgA(+) or IgM(+) plasma cells, B, CD4(+) T and CD8(+) T cells as well as CD4(+) T cells positive for either pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon-γ and interleukin (IL)-12] or for IgA-producing ILs (IL-4, -5, -10 and -6) by cytofluorometry. Antibodies, antibody-secreting cells, and B and T responses in both Peyer's patches and lamina propria were higher in bLf-treated than bLf-untreated mice. The generation of IL-10 and IL-6 CD4(+) T cells in Peyer's patches or TNF-α and IL-12 CD4(+) T cells in lamina propria showed similar response patterns. On days 14 and 28, cytokine/IL CD4(+) T cell responses were increased in Peyer's patches or decreased in lamina propria. The effect of bLf on the elicitation of IgA indicates a potential application of bLf as a nutraceutical to control inflammation in the distal small intestine.

Topics: Administration, Oral; Animals; B-Lymphocytes; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Dietary Supplements; Humans; Immunity, Humoral; Immunoglobulin A; Immunomodulation; Inflammation; Inflammation Mediators; Intestine, Small; Lactoferrin; Male; Mice, Inbred BALB C

Protease-mediated degradation of proteins is critical in a plethora of physiological processes. Neutrophils secrete serine proteases including cathepsin G (CatG), neutrophile elastase (NE), and proteinase 3 (PR3) together with lactoferrin (LF) as a first cellular immune response against pathogens. Here, we demonstrate that LF increases the catalytic activity of CatG at physiological concentration, with its highest enhancing capacity under acidic (pH 5.0) conditions, and broadens the substrate selectivity of CatG. On a functional level, the enzymatic activity of CatG was increased in the presence of LF in granulocyte-derived supernatant. Furthermore, LF enhanced CatG-induced activation of platelets as determined by cell surface expression of CD62P. Consequently, LF-mediated enhancement of CatG activity might promote innate immunity during acute inflammation.

Topics: Allosteric Regulation; Biocatalysis; Cathepsin G; Culture Media, Conditioned; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Granulocytes; Humans; Hydrogen-Ion Concentration; Immunity, Innate; Immunoblotting; Inflammation; Lactoferrin; Leukocyte Elastase; Platelet Activation; Proteolysis; Substrate Specificity

Bovine lactoferrin (bLF) may modulate neonatal intestinal inflammation. Previous studies in intestinal epithelial cells (IECs) indicated that moderate bLF doses enhance proliferation whereas high doses trigger inflammation. To further elucidate cellular mechanisms, we profiled the porcine IEC proteome after stimulation with bLF at 0, 0.1, 1 and 10g/L by LC-MS-based proteomics. Key pathways were analyzed in the intestine of formula-fed preterm pigs with and without supplementation of 10g/L bLF. Levels of 123 IEC proteins were altered by bLF. Low bLF doses (0.1-1g/L) up-regulated 11 proteins associated with glycolysis, energy metabolism and protein synthesis, indicating support of cell survival. In contrast, a high bLF dose (10g/L) up-regulated three apoptosis-inducing proteins, down-regulated five anti-apoptotic and proliferation-inducing proteins and 15 proteins related to energy and amino acid metabolism, and altered three proteins enhancing the hypoxia inducible factor-1 (HIF-1) pathway. In the preterm pig intestine, bLF at 10g/L decreased villus height/crypt depth ratio and up-regulated the Bax/Bcl-2 ratio and HIF-1α, indicating elevated intestinal apoptosis and inflammation. In conclusion, bLF dose-dependently affects IECs via metabolic, apoptotic and inflammatory pathways. It is important to select an appropriate dose when feeding neonates with bLF to avoid detrimental effects exerted by excessive doses.. The present work elucidates dose-dependent effects of bLF on the proteomic changes of IECs in vitro supplemented with data from a preterm pig study confirming detrimental effects of enteral feeding with the highest dose of bLF (10g/L). The study contributes to further understanding on mechanisms that bLF, as an important milk protein, can regulate the homeostasis of the immature intestine. Results from this study urge neonatologists to carefully consider the dose of bLF to supplement into infant formula used for preterm neonates.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Cattle; Cell Cycle Proteins; Cell Survival; Epithelial Cells; Inflammation; Intestinal Mucosa; Lactoferrin; Swine

Lactoferrin (Lf), component of maternal milk, has antioxidant, anti-inflammatory and antimicrobial properties. Neuroprotective effects of Lf on the immature brain have been recently shown in rodent models of intrauterine growth restriction and cerebral hypoxia/ischemia. Here we postulated that Lf could also have beneficial effects on preterm inflammatory brain injury. Lf was supplemented in maternal food during lactation and lipopolysaccharide (LPS) was injected in subcortical white matter of rat pups at postnatal day 3 (P3). Effect of maternal Lf supplementation was investigated 24 h (P4), 4 (P7), or 21 days (P24) after LPS injection mainly on the striatum. Lateral ventricle and brain structures volumes were quantified. Microstructure was evaluated by diffusion tensor imaging, neurite orientation dispersion and density imaging as well as electron microscopy. Neurochemical profile was measured by (1) H-magnetic resonance spectroscopy. GFAP protein, proinflammatory cytokines mRNA expression microglial activation were assessed. Lf displayed neuroprotective effects as shown by reduced LPS-induced ventriculomegaly, brain tissue loss, and microstructural modifications, including myelination deficit. (1) H-MRS neurochemical profile was less altered through an antioxidant action of Lf. Despite the lack of effect on LPS-induced proinflammatory cytokines genes expression and on reactive gliosis, microglia was less activated under Lf treatment. In conclusion, Lf supplemented in food during lactation attenuated acute and long-term cerebral LPS-induced alterations. This provides a new evidence for a promising use of Lf as a preventive neuroprotective approach in preterm encephalopathy. © 2016 BioFactors, 42(3):323-336, 2016.

Topics: Animals; Antioxidants; Brain Injuries; Brain Mapping; Corpus Striatum; Female; Humans; Inflammation; Lactation; Lactoferrin; Lipopolysaccharides; Milk; Neuroprotective Agents; Rats

The aim was to measure concentrations of four neutrophil-derived proteins in meconium as biomarkers describing prenatal environment.. Calprotectin, lactoferrin, myeloperoxidase and PMN-elastase concentrations were measured using ELISA kits in serial meconium portions (n = 81) from 20 healthy neonates.. The highest concentration was for calprotectin (286.5 ± 214.6 µg/g) with a positive correlation (r = 0.75, p < 0.0001) with myeloperoxidase (1.81 ± 1.72 µg/g). For PMN-elastase (1.70 ± 2.69 µg/g) a negative correlation was observed with calprotectin and myeloperoxidase (r = -0.51, p < 0.0001; r = -0.60, p < 0.0001, respectively). Concentration of lactoferrin (45.07 ± 78.53 µg/g) correlated only with that of myeloperoxidese (r = 0.36, p = 0.0009).. Calprotectin, lactoferrin, myeloperoxidase and PMN-elastase concentrations in meconium are interrelated. These proteins may serve as objective biomarkers describing and/or assessing the intrauterine environment.

Topics: Adult; Biomarkers; Birth Weight; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Infant, Newborn; Inflammation; Lactoferrin; Leukocyte Elastase; Leukocyte L1 Antigen Complex; Male; Meconium; Neutrophils; Peroxidase

Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases.

Topics: Amino Acids; Cell Line; Cell Membrane; Extracellular Traps; Gene Silencing; Histones; Humans; Inflammation; Lactoferrin; Leukocyte Elastase; Neutrophils; Protein Transport; Proteolysis; Reactive Oxygen Species; RNA Interference

Lactoferrin (LF) is an 80 kDa glycoprotein which is known for its effects against bacteria, viruses and other pathogens. It also has a high potential in nutrition therapy and welfare of people and a variety of animals, including piglets. The ability to bind lipopolysaccharide (LPS) is one of the described anti-inflammatory mechanisms of LF. Previous studies suggested that cells can be stimulated even by LPS-free LF. Therefore, the aim of our study was to bring additional information about this possibility. Porcine monocyte derived macrophages (MDMF) and human embryonic kidney (HEK) cells were stimulated with unpurified LF in complex with LPS and with purified LF without bound LPS.. Both cell types were stimulated with unpurified as well as purified LF. On the other hand, neither HEK0 cells not expressing any TLR nor HEK4a cells transfected with TLR4 produced any pro-inflammatory cytokine transcripts after stimulation with purified LF. This suggests that purified LF without LPS stimulates cells via another receptor than TLR4. An alternative, TLR4-independent, pathway was further confirmed by analyses of the NF-kappa-B-inducing kinase (NIK) activation. Western blot analyses showed NIK which activates different NFκB subunits compared to LF-LPS signaling via TLR4. Though, this confirmed an alternative pathway which is used by the purified LF free of LPS. This stimulation of MDMF led to low, but significant amounts of pro-inflammatory cytokines, which can be considered as a positive stimulation of the immune system.. Our results suggest that LF's ability is not only to bind LPS, but LF itself may be a stimulant of pro-inflammatory pathways.

Topics: Animals; Cytokines; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Lactoferrin; Lipopolysaccharides; Macrophages; Protein Binding; Protein Serine-Threonine Kinases; Signal Transduction; Swine; Toll-Like Receptor 4

Low-grade inflammation is an underlying feature of obesity and identifying inflammatory markers is crucial to understanding this disease. Therefore, the purpose of this study was twofold: (i) to perform a global microarray analysis and (ii) to investigate the role of lactoferrin (LTF), one of the most altered genes, in relation to obesity in Latino youth.. Non-diabetic Latino youth (71 males/92 females; 15.6 ± 3.2 years) were studied. A subset of 39 participants was randomly selected for global microarray analysis profiling from the whole blood sample. Serum LTF was compared between lean (n = 78) and overweight/obese (n = 85) participants.. Microarray analysis revealed that a total of 1870 probes were altered in expression ≥1.2-fold and P < 0.05 in overweight/obese participants compared with lean. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed significant enrichment for pathways including toll-like receptor (TLR) and B cell receptor signalling pathways. LTF and TLR5 were increased in expression by 2.2 and 1.5 fold, respectively, in the overweight/obese participants. Increased LTF concentrations were significantly associated with high risk of obesity-related phenotypes (all P < 0.05).. Our data suggest that increased LTF is associated with obesity risk among Latino youth. This finding is discordant to what has been shown in adults and suggests that age may modulate the association between LTF and obesity-related health.

Topics: Adolescent; Arizona; Biomarkers; Female; Gene Expression Profiling; Hispanic or Latino; Humans; Inflammation; Lactoferrin; Male; Microarray Analysis; Pediatric Obesity; Phenotype

The optimization of procedure evaluating the severity of inflammatory bowel diseases (IBD) using non-invasive methods.. One hundred and nine children with IBD hospitalized in gastroenterology ward between 2009 and 2011 participated in the study. Activity of the disease was evaluated in each patient. Concentration of three inflammatory markers: dimeric form of tumor pyruvate kinase (M2-PK), calprotectin and lactoferrin was evaluated using immunoenzymatic tests.. Existence of a significant correlation between the faecal level of all tested markers and the stage of clinical activity of the disease was demonstrated in children with IBD, both in Crohn's disease (M2-PK p<0.01; calprotectin p=0.005; lactoferrin p<0.01) and in ulcerative colitis group (M2-PK p<0.01; calprotectin p=0.004; lactoferrin p<0.01). A significant difference in the level of markers was found between children with unclassified colitis and the group of patients with ulcerative colitis and Crohn's disease, but there was no difference between Crohn's disease and ulcerative colitis. The increase in the level of one marker correlated with increasing level of other markers (p<0.01). Faecal markers seem to correlate well with majority of indicators of inflammatory condition in blood.. Measuring M2-PK, lactoferrin and calprotectin levels in faeces seem to be a useful indicator of the level of disease activity in children with IBD.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Feces; Female; Humans; Inflammation; Inflammatory Bowel Diseases; Lactoferrin; Leukocyte L1 Antigen Complex; Male; Pyruvate Kinase

Helicobacter pylori (H. pylori) is a life-threatening pathogen which causes chronic gastritis, gastric ulcers and even stomach cancer. Treatment normally involves bacterial eradication; however, this type of treatment only has a rate of effectiveness of <80%. Thus, it is a matter of some urgency to develop new therapeutic strategies. Lactoferrin, a member of the transferrin family of iron-binding proteins, has been proven to be effective in removing a vast range of pathogens, including H. pylori. In the present study, we examined the effectiveness of recombinant human lactoferrin (rhLf) isolated from transgenic goats as a treatment for H. pylori in vitro and in vivo. For the in vivo experiments, BALB/c mice received an intragastric administration of 0.1 ml of a suspension of H. pylori. The mice were then divided into 4 groups: group A, treated with saline; group B, treated with 1.5 g of rhLF; group C, treated with the standard triple therapy regimen; and group D, treated with the standard triple therapy regimen plus.5 g of rhLF. Following sacrifice, the stomach tissues of the mice were histologically examined for the presence of bacteria. For the in vitro experiments, the bacteria were cultured in BHI broth and RT-qPCR and western blot analysis were carried out to determine the mRNA and protein levels of virulence factors (CagA and VacA) in the cultures. Our results revealed that rhLf not only inhibited the growth of H. pylori, but also suppressed the expression of two major virulence factors. Moreover, rhLf markedly increased bacterial eradication and effectively reduced the inflammatory response when combined with the standard triple therapy regimen. These results provide evidence supporting the use of rhLF as an adjuvant to traditional therapeutic strategies in the treatment of H. pylori.

Topics: Animals; Anti-Bacterial Agents; Drug Synergism; Gene Expression Regulation, Bacterial; Goats; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Lactoferrin; Mice; Mice, Inbred BALB C; Recombinant Proteins; Stomach

The aim of this study was to analyze the usefulness of fecal lactoferrin in the diagnosis and monitoring of inflammatory bowel disease (IBD) in children. The study included 52 children with IBD (24 with Crohn's disease and 28 with ulcerative colitis) aged between 0.92 and 18 years, and 41 IBD-free controls of similar age. Fecal concentration of lactoferrin was determined with a quantitative immunoenzymatic test. Fecal concentration of lactoferrin in children with IBD was significantly higher than in the controls. The cut-off value of fecal lactoferrin concentration optimally distinguishing between the children with IBD and the controls was identified as 13 μg/g. The sensitivity and specificity of this cut-off value equaled 80.7% and 92.7%, respectively, and its positive and negative prognostic values were 96.8% and 63.3%, respectively. Patients diagnosed with moderate Crohn's disease had significantly higher fecal concentrations of lactoferrin than children with the mild or inactive disease. Similarly, children with moderate ulcerative colitis showed significantly higher fecal concentrations of lactoferrin than individuals with the mild condition. No significant relationship was found between the fecal concentration of lactoferrin and the severity of endoscopic lesions. Patients with IBD and a positive result of fecal occult blood test were characterized by significantly higher concentrations of lactoferrin than the individuals with IBD and a negative result of this test. In conclusion, fecal concentration of lactoferrin seems to be a useful parameter for diagnosis and monitoring of IBD in children.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Feces; Female; Humans; Immunoenzyme Techniques; Infant; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Lactoferrin; Male; Predictive Value of Tests; Prognosis

This paper aimed to investigate the molecular mechanisms associated with angiotensin-converting enzyme (ACE)-inhibitory peptide activity involved in vascular extracellular matrix (ECM) remodeling. Therefore, changes in collagen fibers, elastic fibers and laminin were assessed in the left common carotid artery (LCCA).. We selected 10-week-old male spontaneously hypertensive rats to study the expression levels of matrix metalloproteinases (MMPs), transforming growth factor, angiotensin (Ang) II and nuclear factor (NF)-p65 in the wall of carotid arteries.. Compared to the control group, laminin expression was significantly increased (p < 0.05) in the vascular endothelium of the LAP (a homemade ACE-inhibitory peptide, named by ourselves) group, whereas the percentage of elastic/collagen fibers in the LCCA vascular area was significantly decreased (p < 0.0001) in the LAP group. Immune blots of MMP-2, MMP-9, NF-p65 and AngII were significantly reduced in the LCCA wall in the LAP group.. Vascular ECM remodeling may be related to the inhibitory action of LAP on ECM deposition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Carotid Artery, Common; Collagen; Elastic Tissue; Extracellular Matrix; Heart Rate; Inflammation; Lactoferrin; Laminin; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Peptide Fragments; Random Allocation; Rats; Rats, Inbred SHR; Transcription Factor RelA; Transforming Growth Factor beta1

In human and mice adipose tissue, lactoferrin (LTF) has been found to be associated with increased adipogenesis and decreased inflammatory markers. Here, we aimed to investigate the effects of LTF knockdown (KD) in human adipocyte differentiation. In addition, the effects of exogenous LTF administration and iron chelation [using deferoxamine (DFO, 10 μM)] were tested. In both subcutaneous and visceral pre-adipocytes, LTF KD led to decrease significantly adipogenic, lipogenic and insulin signalling-related gene expression and a significant increase in the gene expression of inflammatory mediators. Human lactoferrin (hLf, 1 μM) administration led to recover adipocyte differentiation in LTF KD pre-adipocytes. Interestingly, iron chelation triggered similar effects to LTF KD, decreasing significantly adipogenic gene expressions. Of note, DFO (10 μM) and hLf (1 and 10 μM) co-administration led to a dose-dependent recovery of adipocyte differentiation. These new data reveal that endogenous LTF biosynthesis during human adipocyte differentiation is essential to achieve this process, possibly, modulating adipocyte iron homoeostasis. hLf administration might be a useful therapeutic target in obesity-associated adipose tissue dysfunction.

Topics: Adipocytes; Adipogenesis; Biomarkers; Deferoxamine; Gene Knockdown Techniques; Humans; Inflammation; Iron; Iron Chelating Agents; Lactoferrin

Malignant melanoma is the most aggressive and deadliest form of skin cancer due to its highly metastatic potential, which calls for new and improved therapies. Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line of defense against pathogens, and several CAPs have shown promising potential as novel anticancer agents. Structure-activity relationship studies on the CAP bovine lactoferricin allowed us to de novo design short chemically modified lytic anticancer peptides. In the present study, we investigated the in vivo antitumor effects of LTX-315 against intradermally established B16 melanomas in syngeneic mice. Intratumoral administration of LTX-315 resulted in tumor necrosis and the infiltration of immune cells into the tumor parenchyma followed by complete regression of the tumor in the majority of the animals. LTX-315 induced the release of danger-associated molecular pattern molecules such as the high mobility group box-1 protein in vitro and the subsequent upregulation of proinflammatory cytokines such as interleukin (IL) 1β, IL6 and IL18 in vivo. Animals cured by LTX-315 treatment were protected against a re-challenge with live B16 tumor cells both intradermally and intravenously. Together, our data indicate that intratumoral treatment with LTX-315 can provide local tumor control followed by protective immune responses and has potential as a new immunotherapeutic agent.

Topics: Animals; Antimicrobial Cationic Peptides; Blotting, Western; Cattle; Cells, Cultured; Cytokines; Female; Hemolysis; Humans; Inflammation; Inflammation Mediators; Lactoferrin; Lymphocytes, Tumor-Infiltrating; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; Peptide Fragments

Topics: Asthma; Case-Control Studies; Cytokines; Disease Progression; Eosinophils; GPI-Linked Proteins; Humans; Immunohistochemistry; Inflammation; Interleukin-13; Lactoferrin; Lectins; Mucus; Up-Regulation

This study investigated the ability of aerosolized bovine lactoferrin (bLF) to protect the lungs from injury induced by chronic hyperoxia. Female CD-1 mice were exposed to hyperoxia (FiO2 = 80 %) for 7 days to induce lung injury and fibrosis. The therapeutic effects of bLF, administered via an aerosol delivery system, on the chronic lung injury induced by this period of hyperoxia were measured by bronchoalveolar lavage, lung histology, cell apoptosis, and inflammatory cytokines in the lung tissues. After exposure to hyperoxia for 7 days, the survival of the mice was significantly decreased to 20 %. The protective effects of bLF against hyperoxia were further confirmed by significant reductions in lung edema, total cell numbers in bronchoalveolar lavage fluid, inflammatory cytokines (IL-1β and IL-6), pulmonary fibrosis, and apoptotic DNA fragmentation. The aerosolized bLF protected the mice from oxygen toxicity and increased the survival fraction to 66.7 % in the hyperoxic model. The results support the use of an aerosol therapy with bLF in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure or chronic obstructive pulmonary disease.

Topics: Administration, Inhalation; Animals; Apoptosis; Cattle; Cytokines; Disease Models, Animal; Drug Delivery Systems; Female; Humans; Hyperoxia; Immunologic Factors; Inflammation; Lactoferrin; Lung Injury; Mice; Mice, Inbred ICR; Pulmonary Fibrosis

Nonresolving inflammatory processes affect all stages of carcinogenesis. Lactoferrin, a member of the transferrin family, is involved in the innate immune response and anti-inflammatory, anti-microbial, and anti-tumor activities. We previously found that lactoferrin is significantly down-regulated in specimens of nasopharyngeal carcinoma (NPC) and negatively associated with tumor progression, metastasis, and prognosis of patients with NPC. Additionally, lactoferrin expression levels are decreased in colorectal cancer as compared with normal tissue. Lactoferrin levels are also increased in the various phases of inflammation and dysplasia in an azoxymethane-dextran sulfate sodium (AOM-DSS) model of colitis-associated colon cancer (CAC). We thus hypothesized that the anti-inflammatory function of lactoferrin may contribute to its anti-tumor activity. Here we generated a new Lactoferrin knockout mouse model in which the mice are fertile, develop normally, and display no gross morphological abnormalities. We then challenged these mice with chemically induced intestinal inflammation to investigate the role of lactoferrin in inflammation and cancer development. Lactoferrin knockout mice demonstrated a great susceptibility to inflammation-induced colorectal dysplasia, and this characteristic may be related to inhibition of NF-κB and AKT/mTOR signaling as well as regulation of cell apoptosis and proliferation. Our results suggest that the protective roles of lactoferrin in colorectal mucosal immunity and inflammation-related malignant transformation, along with a deficiency in certain components of the innate immune system, may lead to serious consequences under conditions of inflammatory insult.

Topics: Animals; Apoptosis; Azoxymethane; Cell Proliferation; Colitis; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Down-Regulation; Gene Knockout Techniques; Humans; Inflammation; Lactoferrin; Male; Mice; NF-kappa B; Signal Transduction

To investigate which air pollution characteristics are associated with biomarkers for acute nasal airway inflammation in healthy subjects. We hypothesised that associations would be strongest for oxidative potential (OP) of particles.. 31 volunteers were exposed to ambient air pollution at five sites in The Netherlands: two traffic sites, an underground train station, a farm and an urban background site. Each subject visited at least three sites between March and October 2009 and was exposed for 5 h per visit including exercise for 20 min every hour (h). Air pollution measurements during this 5-h-period included particulate matter (PM) mass concentration, elemental composition, elemental and organic carbon (OC), particle number concentration, OP, endotoxins, O3 and NO2. Pro-inflammatory biomarkers were measured before, 2 and 18 h postexposure, including cytokine IL-6 and IL-8, protein and lactoferrin in nasal lavage (NAL) as well as IL-6 in blood. One- and two-pollutant mixed models were used to analyse associations between exposure and changes in biomarkers.. In two-pollutant models, cytokines in NAL were positively associated with OC, endotoxin and NO2; protein was associated with NO2; and lactoferrin was associated with all PM characteristics that were high at the underground site. In blood, associations with OC and endotoxin were negative.. We observed no consistent effects in two-pollutant models for PM mass concentration and OP. Instead, we found consistent associations with nasal inflammatory markers for other PM characteristics, specifically OC, endotoxin and NO2.

Topics: Adult; Air Pollutants; Air Pollution; Biomarkers; Carbon; Endotoxins; Exercise; Female; Humans; Inflammation; Inflammation Mediators; Inhalation Exposure; Interleukins; Lactoferrin; Male; Netherlands; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Proteins; Rhinitis; Young Adult

Salivary and serum levels of lactoferrin and ferritin were measured in patients with pulmonary tuberculosis and patients with other nonspecific respiratory diseases. Measurements of lactoferrin in biological media and particularly in the serum of patients with pulmonary tuberculosis proved to be a highly informative test for monitoring the disease course, i.e. for evaluation of inflammatory process activity. Ferritin level can serve as an indicator of tissue destruction during inflammation and of the course of rehabilitation processes.

Topics: Biomarkers; Ferritins; Humans; Inflammation; Lactoferrin; Pneumonia; Saliva; Tuberculosis, Pulmonary

Lactoferrin (LF) can downregulate allergic airway inflammation in asthma. However, the in vivo effect of exogenous LF on allergic rhinitis (AR), a disease attributed to airway inflammation, has yet to be determined. We investigated the effect of intranasal administration recombinant human (rh) LF and its underlying mechanisms on AR in BALB/c mice. Multiple parameters of allergic responses were evaluated to determine the effect of rhLF. We found that the number of eosinophils and goblet cells, as well as mRNA and protein expression of type 2 helper T (Th2), Th17 and regulatory T (Treg) cells in the nasal cavity, was significantly upregulated in AR mice compared with the controls, Conversely, administration of rhLF prior to or after intranasal ovalbumin challenge markedly downregulated these same parameters. Th1-specific mRNA and protein expression in the nasal cavity of the controls was not different from that in AR mice, but expression significantly increased with rhLF treatment. The mRNA and protein expression of endogenous LF in the nasal cavity was significantly downregulated in AR mice compared with the controls. However, after rhLF treatment, endogenous LF mRNA and protein expression was significantly upregulated. Exogenous rhLF inhibited allergic inflammation in AR mice, most likely by promoting the endogenous LF expression and skewing T cells to a Th1, but not a Th2 and Th17 phenotype in the nasal mucosa. Our findings suggest that rhLF treatment may be a novel therapeutic approach for prevention and treatment AR.

Topics: Administration, Intranasal; Animals; Cytokines; Disease Models, Animal; Eosinophils; Goblet Cells; Inflammation; Lactoferrin; Lymphocyte Count; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; RNA, Messenger; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; Th2 Cells

Lactoferrin is an antimicrobial and immunomodulatory protein that is produced in high quantities in human milk and aids in the gastrointestinal (GI) maturation of infants. Beneficial health effects have been observed when supplementing human and animal diets with lactoferrin. A herd of genetically engineered cattle that secrete recombinant human lactoferrin in their milk (rhLF-milk) have been generated which provide an efficient production system and ideal medium for rhLF consumption. The effects of consumption of rhLF-milk were tested on young pigs as an animal model for the GI tract of children. When comparing rhLF-milk fed pigs to non-transgenic milk fed pigs (control), we observed that rhLF-milk fed pigs had beneficial changes in circulating leukocyte populations. There was a significant decrease in neutrophils (p = 0.0036) and increase in lymphocytes (p = 0.0017), leading to a decreased neutrophil to lymphocyte ratio (NLR) (p = 0.0153), which is an indicator of decreased systemic inflammation. We also observed changes in intestinal villi architecture. In the duodenum, rhLF-milk fed pigs tended to have taller villi (p = 0.0914) with significantly deeper crypts (p < 0.0001). In the ileum, pigs consuming rhLF-milk had villi that were significantly taller (p = 0.0002), with deeper crypts (p < 0.0001), and a thinner lamina propria (p = 0.0056). We observed no differences in cytokine expression between rhLF-milk and control-milk fed pigs, indicating that consumption of rhLF-milk did not change cytokine signaling in the intestines. Overall favorable changes in systemic health and GI villi architecture were observed; indicating that consumption of rhLF-milk has the potential to induce positive changes in the GI tract.

Topics: Animals; Animals, Genetically Modified; Cattle; Cytokines; Duodenum; Enterobacteriaceae; Escherichia coli; Female; Food, Genetically Modified; Gastrointestinal Tract; Humans; Ileum; Inflammation; Lactoferrin; Leukocytes; Male; Milk; Swine

Lactoferrin is considered an epithelial protein present in different gland secretions. Administration of exogenous lactoferrin is also known to modulate adipogenesis and insulin action in human adipocytes. Here, we aimed to investigate lactoferrin gene expression (real-time polymerase chain reaction) and protein (enzyme-linked immunosorbent assay) levels in human (n=143) and mice adipose tissue samples, in adipose tissue fractions and during human preadipocyte and 3T3-L1 cell line differentiation, evaluating the effects of inducers (rosiglitazone) and disruptors (inflammatory factors) of adipocyte differentiation. Lactoferrin (LTF) gene and protein were detectable at relatively high levels in whole adipose tissue and isolated adipocytes in direct association with low-density lipoprotein-related protein 1 (LRP1, its putative receptor). Obese subjects with type 2 diabetes and increased triglycerides had the lowest levels of LTF gene expression in subcutaneous adipose tissue. Specifically, LTF gene expression was significantly increased in adipocytes, mainly from lean subjects, increasing during differentiation in parallel to adipogenic genes and gene markers of lipid droplets. The induction or disruption of adipogenesis led to concomitant changes (increase and decrease, respectively) of lactoferrin levels during adipocyte differentiation also in parallel to gene markers of adipogenesis and lipid droplet development. The administration of lactoferrin led to autopotentiated increased expression of the LTF gene. The decreased lactoferrin mRNA levels in association with obesity and diabetes were replicated in mice adipose tissue. In conclusion, this is the first observation, to our knowledge, of lactoferrin gene expression in whole adipose tissue and isolated adipocytes, increasing during adipogenesis and suggesting a possible contribution in adipose tissue physiology through LRP1.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Adult; Animals; Biomarkers; Female; Fibroblasts; Humans; Inflammation; Lactoferrin; Male; Mice; Middle Aged

Entamoeba histolytica is a protozoan parasite that causes amoebiasis, an illness that affects many people around the world. We have previously reported that lactoferrin is able to kill E. histolytica in in vitro cultures. The aim of the present study was to evaluate the therapeutic effect of orally administered bovine lactoferrin in the control of intestinal amoebiasis of susceptible C3H/HeJ mice. The results showed that 20 mg lactoferrin/kg orally administered each day for 1 week was able to eliminate the infection in 63% of the mice, since neither trophozoites nor evidence of epithelial damage and (or) swelling were found in tissue sections of the cecum. The rest of the treated animals (37%) showed a decrease in trophozoite numbers and mucus secreted to the lumen, as compared with untreated and infected mice (p < 0.05). By immunohistochemistry, the profile of secreted cytokines in the cecum revealed that infected but untreated animals showed a mixed Th1/regulatory cytokines profile, whereas the cecum of mice treated (cured) showed a Th2 cytokine profile (IL-4) and expression of the multifunctional IL-6. In addition, cytokines and increasing cecal production of total IgA antibodies were found associated with little inflammation and disease control observed in the cecum of lactoferrin-treated animals. These results suggest that oral administration of lactoferrin can control intestinal amoebic infection probably by killing amoebas or favoring their removal and reestablish the antiinflammatory intestinal environment.

Topics: Administration, Oral; Amebicides; Animals; Cattle; Cecum; Cytokines; Drug Evaluation, Preclinical; Entamoeba histolytica; Entamoebiasis; Host-Parasite Interactions; Immunoglobulin A; Inflammation; Lactoferrin; Mice; Mice, Inbred C3H; Th2 Cells; Treatment Outcome; Trophozoites

To determine gastric tissue lactoferrin (Lf) levels of Helicobacter pylori- (Hp-) positive and -negative patients and its effect on anemia.. Cases in which initial presentation was of abdominal pain and that were Hp-positive at endoscopy were included. Hp-positive cases and -negative controls were divided into two groups.. The study included 64 cases (average: 10.2 ± 0.4 years, 39 male and 25 female). Lf levels were subsequently studied on 61 cases. 45 (73.8%) of these were Hp-positive, while 16 (22.2%) were Hp-negative. In Hp-positive cases, mean staining percentages and density of glands in the antral mucosa were 45.5 ± 4.7% and 1.9 ± 0.1, respectively. Hp-negative cases showed significantly different values of 17.8 ± 4.5% and 1.3 ± 0.2, respectively. Hemoglobin and serum ferritin values of Hp-positive cases were 12.7 ± 0.2 g/dL and 32.5 ± 2 ng/mL, but these were comparable with Hp-negative cases (12.6 ± 0.1 g/dL and 30.7 ± 4.4 ng/mL).. Tissue Lf was significantly higher in Hp-positive cases compared to Hp-negative cases, but no difference was observed between the two groups with regards to hemoglobin and ferritin level. As a result, it is difficult to say that this rise in Lf plays a role in the development of iron deficiency anemia in Hp-positive patients.

Topics: Adolescent; Anemia, Iron-Deficiency; Child; Child, Preschool; Endoscopy; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Lactoferrin; Male; Pyloric Antrum

The content of alpha-macroglobulin associated with pregnancy, alpha2-glycoprotein, alpha1-antitripsin, and lactolerrin in blood serum of pregnant women and umbilical serum under hydramnion and risk of development of intrauterine infection of fetus is investigated. It is demonstrated that in case ofpresence in blood of pregnant woman of G-antibodies to C. trachomatis under low titers (1:20, 1:40) the increase of levels of alpha-macroglobulin, alpha2-glycoprotein, al-antitripsin and especially of lactoferrin in serum of pregnant women testifies the high risk of presence of intrauterine infection of fetus and probability of birth of child with low values on Apgar scale.

Topics: alpha 1-Antitrypsin; alpha-Macroglobulins; Apgar Score; Chlamydia Infections; Chlamydia trachomatis; Female; Humans; Infant, Newborn; Inflammation; Lactoferrin; Polyhydramnios; Pregnancy; Pregnancy Complications, Infectious; Pregnancy-Associated alpha 2-Macroglobulins; Prognosis; Uterus

At the whole organ level, degenerative mechanisms in bone and cartilage are primarily attributed to modifications in loading pattern. Either a change in magnitude or location can initiate a degenerative path. At the micro scale we often see changes in structure such as porosity increase in bone and fibrillation in cartilage. These changes contribute to a reduced structural integrity that weakens the bulk strength of tissue. Finally, at the cell level we have modeling and remodeling pathways that may be disrupted through disease, drugs and altered stimulus from the micro and macro scales. In order to understand this entire process and the roles each level plays a multiscale modeling framework is necessary. This framework can take whole body loadings and pass information through finer spatial scales in order to understand how everyday dynamic movements influence micro and cellular response. In a similar manner, cellular and microstructural processes regulate whole bulk properties and modify whole organ strength. In this study we highlight the multiscale links developed as part of the open-source ontologies for the Physiome Project using the lower limb as an example. We consider the influence of remodeling in (i) anabolic treatments in cortical bone; and (ii) subchondral bone and cartilage degeneration.

Topics: Aged; Anterior Cruciate Ligament; Anthropometry; Bone and Bones; Bone Remodeling; Bone Resorption; Cartilage, Articular; Computer Simulation; Gait; Humans; Imaging, Three-Dimensional; Inflammation; Lactoferrin; Magnetic Resonance Imaging; Models, Anatomic; Models, Biological; Osteoarthritis; Osteoporosis; Porosity

Lactoferrin (Lf) is known to have anti-cancer and anti-inflammatory activities; however, its therapeutic mechanism has not been defined. In this study, to explain the therapeutic mechanism of Lf, we examined the effect of Lf on endothelial cell activation, leukocyte integration, and angiogenesis in vitro.. Endothelia-leukocyte adhesion assays were used to assess primary cultures of bovine aortic endothelial cells (BAECs) activation following LPS treatment. The mRNA expression of ICAM-1 and proinflammatory cytokines was measured using RT-PCR. Each step of angiogenesis was evaluated in vitro, including endothelial cell proliferation, migration, and tube formation. Proliferation was examined using WST-1 and BrdU incorporation assays, while wound migration assays were used to evaluate cell migration; capillary-like tube formation assays on Matrigel were used to assess tube formation.. Lf reduced the adhesion of human monocyte-like THP-1 cells to BAECs by 45%. Lf also reduced mRNA expression of ICAM-1 and proinflammatory cytokines in BAECs. Lf significantly inhibited BAEC proliferation, migration, and tube formation.. Lf exerted a potent effect on BAEC activation, suggesting that it might function via an endothelia-based mechanism in the treatment of various diseases, including rheumatoid arthritis and cancer.

Topics: Animals; Aorta; Cattle; Cell Adhesion; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Endothelium, Vascular; Inflammation; Lactoferrin; Leukocytes; Monocytes; Neovascularization, Pathologic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Lactoferrin has been associated with insulin sensitivity in vivo and in vitro studies. We aimed to test the effects of lactoferrin on human subcutaneous and visceral preadipocytes. Human subcutaneous and visceral preadipocytes were cultured with increasing lactoferrin (hLf, 0.1, 1, 10 μM) under differentiation conditions. The effects of lactoferrin on adipogenesis were studied through the expression of different adipogenic and inflammatory markers, AMPK activation and Retinoblastoma 1 (RB1) activity. The response to insulin was evaluated through (Ser473)AKT phosphorylation. In both subcutaneous and visceral preadipocytes, lactoferrin (1 and 10 μM) increased adipogenic gene expressions and protein levels (fatty acid synthase, PPARγ, FABP4, ADIPOQ, ACC and STAMP2) and decreased inflammatory markers (IL8, IL6 and MCP1) dose-dependently in parallel to increased insulin-induced (Ser473)AKT phosphorylation. In addition to these adipogenic effects, lactoferrin decreased significantly AMPK activity (reducing (pThr172)AMPK and (pSer79)ACC) and RB1 activity (increasing the (pser807/811)RB1/RB1 ratio). In conclusion, these results suggest that lactoferrin promotes adipogenesis in human adipocytes by enhancing insulin signaling and inhibiting RB1 and AMPK activities.

Topics: Adipocytes; Adipogenesis; AMP-Activated Protein Kinases; Biomarkers; Cell Differentiation; Dose-Response Relationship, Drug; Gene Expression; Genes, Regulator; Humans; Inflammation; Lactoferrin; Phosphorylation; PPAR gamma; Retinoblastoma Protein

Pathogenic bacteria colonize the airways of 30% to 40% of patients with COPD and cause approximately 50% of exacerbations. New strains of nontypeable Haemophilus influenzae (NTHI) and Moraxella catarrhalis are associated with exacerbations. Antimicrobial protein/peptides (AMPs) play important roles in innate lung defense against pathogens. To our knowledge, the changes in AMP baseline levels in respiratory secretions during bacterial colonization and exacerbation have not been described. The objective of this study was to elucidate the effects of the acquisition of a new strain of pathogenic bacteria on the airway levels of AMPs in patients with COPD.. One hundred fifty-three samples from 11 patients were selected from COPD sputum samples collected prospectively over 6 years. Samples were grouped as culture-negative (no pathogenic bacteria), colonization, and exacerbation due to new strains of NTHI and M catarrhalis. Levels of lysozyme, lactoferrin, LL-37, and secretory leukocyte protease inhibitor (SLPI) were measured by enzyme-linked immunosorbent assay and compared among groups by paired analysis.. Compared with baseline, sputum lysozyme levels were significantly lower during colonization and exacerbation by NTHI (P = .001 and P = .013, respectively) and M catarrhalis (P = .007 and P = .018, respectively); SLPI levels were lower with exacerbation due to NTHI and M catarrhalis (P = .002 and P = .004, respectively), and during colonization by M catarrhalis (P = 032). Lactoferrin levels did not change significantly; LL-37 levels were higher during exacerbation by NTHI and M catarrhalis (P = .001 and P = .018, respectively).. Acquisition of NTHI and M catarrhalis is associated with significant changes in airway levels of AMPs, with larger changes in exacerbation. Airway AMP levels are likely to be important in pathogen clearance and clinical outcomes of infection in COPD.

Topics: Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; beta-Defensins; Cathelicidins; Disease Progression; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Inflammation; Lactoferrin; Male; Middle Aged; Moraxella catarrhalis; Moraxellaceae Infections; Muramidase; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Secretory Leukocyte Peptidase Inhibitor; Sputum

Fecal lactoferrin is the direct expression of intestinal inflammation in Crohn's disease (CD). The aim of this study was to analyze the in vivo intimate correlation between intestinal and systemic inflammation in CD patients in clinical remission following bowel resection. The secondary end point was to evaluate the prognostic value of lactoferrin levels and serum cytokines in terms of need of surgery for recurrence in these patients.. Fecal lactoferrin and serum cytokine (interleukin (IL)-1beta, IL-6, IL-12, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta1) levels were assessed; hematological and biochemical investigations were carried out, and Crohn's Disease Activity Index was evaluated in the 36 patients who had undergone bowel resection. The prognostic value of lactoferrin and cytokine levels in terms of surgical recurrence was assessed by re-calling patients after 24 months from the enrolment in the study.. All patients, evaluated after a follow-up of 36 +/- 5 months, were in clinical remission. Fecal lactoferrin levels were found to be significantly correlated with IL-6 (R = 0.431, p = 0.025) and C-reactive protein (CRP; R = 0.507, p = 0.007), while no correlation was observed between lactoferrin and IL-1beta, IL-12, TNF-alpha, or TGF-beta1. Reoperation for anastomotic recurrence tended to occur significantly more frequently in patients with higher IL-6 (p = 0.10).. Subclinical intestinal inflammation, expressed by fecal lactoferrin, seems to keep the systemic inflammation alive in CD patients through the IL-6-CRP cascade. IL-6 seems to be predictive of the outcome of CD patients undergoing surgery.

Topics: Adult; Biomarkers; C-Reactive Protein; Colon; Crohn Disease; Feces; Female; Humans; Ileum; Inflammation; Interleukin-12; Interleukin-1beta; Interleukin-6; Lactoferrin; Male; Middle Aged; Prognosis; Recurrence; Transforming Growth Factor beta1

The lactoferrin gene is known to be expressed either constitutively or under inducible conditions such as hormonal stimuli or inflammation. Its transcription from alternative promoters leads to two products, lactoferrin (Lf) and delta-lactoferrin (DeltaLf) mRNAs the expressions of which are altered during oncogenesis. The comparison of the two enhancer/promoter regions revealed that the two isoforms might be differentially trans-activated. Nevertheless, concomitant expression of both transcripts has been found in some normal tissues and in a subset of breast cancer cell lines and biopsies. Moreover, we found putative inflammatory response elements in both P1 and P2 promoter regions suggesting that both Lf and DeltaLf might be upregulated under inflammatory stimuli. Therefore, a duplex Taqman gene expression assay has been developed and used to profile mRNA expression of the Lf gene in the case of cancer and under inflammatory conditions. Discrimination between the two transcripts is achieved by using a primer pairs/probe set within exon 1beta for DeltaLf and a primer pairs/probe set within exon 1 and exon 2 for Lf. In this study, we confirmed that Lf/DeltaLf Taqman gene expression assay is a powerful tool to investigate the expression of both Lf and DeltaLf transcripts. We also showed that lymphocytes and leukocytes isolated from fresh human blood expressed an extremely high level of DeltaLf messengers. An extensive series of cancer cell lines has been studied confirming that both P1 and P2 promoter regions of the Lf gene are downregulated or silenced in the case of cancer. Furthermore, using stimulation by bacterial lipopolysaccharides (LPS), we showed that in MDA-MB-231 and HT-29 epithelial cells, Lf expression is strongly increased with a higher expression level in MDA-MB-231 whereas DeltaLf expression is not. These results suggest that the NF-kappaB/cRel response elements present in the P1 promoter region are functional whereas those present in the P2 promoter region are not and show that DeltaLf is not regulated in inflammatory conditions.

Topics: Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Inflammation; Lactoferrin; Lipopolysaccharides; Neoplasms; Promoter Regions, Genetic; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Lactoferrin (LF) has in vitro antimicrobial activity against Gram-negative bacteria. Salmonella enterica subsp. enterica serovar Typhimurium causes systemic infection and acute diarrhea in humans, mainly in children younger than 2 years of age. The aim of the study was to determine the in vivo effect of bovine LF in Salmonella ser. Typhimurium infection in mice. 58 BALB/c mice were employed. Two hours before the infection with 300 microl of 10(7) CFU of Salmonella ser. Typhimurium, 29 mice received LF (2 mg) and 29 placebo (buffer). After the infection, the mice received LF (10 mg/ml) ad libitum or buffer, respectively, for 7 days. Mortality, weight and clinical signs (piloerection, hunched position and reduced movement) were monitored daily. The degree of inflammation and necrosis in the intestine, liver, spleen and brain were studied with a blinded observer. The mortality in the control group (8/29) was higher than in the LF group (1/29) (Kapplan Meier P < 0.05). From the third day post-infection the control group were significantly more symptomatic (P < 0.05). The blood culture for Salmonella spp. was positive for all mice studied in the control group (17/17), but positive in the LF group in only 6/17 animals (P < 0.05). In the LF group, the pathologic studies show less inflammation and focal necrosis in the four organs studied, with the greatest difference found in the intestine. Bovine LF protects against Salmonella ser. Typhimurium infection in mice, reducing the severity, mortality and the degree of inflammation of this infection.

Topics: Animals; Anti-Bacterial Agents; Body Weight; Cattle; Female; Inflammation; Lactoferrin; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Salmonella Infections, Animal; Salmonella typhimurium; Survival Rate

Crohn's disease and ulcerative colitis have a feature in common (i.e., chronic inflammation). Their clinical management requires repeated assessments; endoscopy with histological examination remains the gold standard for detecting and quantifying intestinal inflammation. An ideal marker should be quick and easy to obtain noninvasively, and should be inexpensive and reproducible. Several laboratory tests have been studied but, to date, a disease marker is not yet available. A combination of signs and symptoms, laboratory findings and imaging techniques is consequently still needed for assessing disease activity and prognosis. In recent years, research has drawn attention to fecal markers owing to their specificity for intestinal inflammation, ease of sample collection, availability of commercial immunoassays and convenience. Biological markers have been used to assess inflammatory bowel disease patients for the purposes of their clinical management, monitoring disease activity, predicting relapses, assessing prognosis and monitoring response to treatment.

Topics: Biomarkers; Diagnosis, Differential; Feces; Humans; Inflammation; Inflammatory Bowel Diseases; Lactoferrin; Leukocyte L1 Antigen Complex; Predictive Value of Tests; Prognosis

The pathogenesis of diabetes and atherosclerosis is linked through inflammation. Neutrophils contribute to atherosclerotic plaque development, and are dysfunctional in diabetes. The aim of this study was to compare the predictive values of two neutrophil degranulation products, myeloperoxidase and lactoferrin, on long-term risk for fatal ischemic heart disease in persons with newly diagnosed diabetes and controls.. Prospective population-based cohort study.. In 1984-1986, a large population study, HUNT 1, was conducted in Norway. Previously unknown diabetes was diagnosed in 205 persons. A matched control group without diabetes was selected from the HUNT 1.. Fatal ischemic heart disease was registered until 2004. Baseline serum was analysed for myeloperoxidase and lactoferrin. Cox regression analysis with adjustments for age, gender, hypertension, body mass index, established cardiovascular disease and total cholesterol was used to estimate hazard ratios for fatal ischemic heart disease.. In the diabetes group (200 subjects), the two highest tertiles of lactoferrin predicted fatal ischemic heart disease, hazard ratio 2.54 (95% CI, 1.00-6.45) and 4.06 (1.72-9.60). Myeloperoxidase did not predict death from ischemic heart disease in subjects with diabetes. In the controls (198 subjects), none of the biomarkers predicted fatal ischemic heart disease.. Increased baseline concentration of lactoferrin strongly predicted the long-term risk for fatal ischemic heart disease in patients with newly diagnosed diabetes. Based on the literature, we hypothesize that the increased concentrations may reflect neutrophil priming caused by hyperglycemia.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Inflammation; Lactoferrin; Male; Myocardial Ischemia; Neutrophils; Peroxidase; Proportional Hazards Models; Risk Factors; Time Factors

Chronic wounds associated with vascular disease, diabetes mellitus, or aging are leading causes of morbidity in western countries and represent an unresolved clinical problem. The development of innovative strategies to promote tissue repair is therefore an important task that requires a more thorough analysis of the underlying molecular pathophysiology. We propose that the understanding of the complex biological events that control tissue repair or its failure largely benefits from a broad analytical approach as provided by novel proteomic methodologies. Here we present the first comparative proteome analysis of wound exudates obtained from normal healing or nonhealing (venous leg ulcer) human skin wounds. A total of 149 proteins were identified with high confidence. A minority of proteins was exclusively present in exudate of the healing wound (23 proteins) or the nonhealing wound (26 proteins). Of particular interest was the differential distribution of specific proteins among the two different healing phenotypes. Whereas in the exudate obtained from the healing wound mediators characteristic for tissue formation were abundantly present, in the exudate obtained from the nonhealing wound numerous mediators characteristic for a persistent inflammatory and tissue destructive response were identified. Furthermore, the study also revealed interesting results regarding the identification of new proteins with yet unknown functions in skin repair. This analysis therefore represents an important basis for the search for potential biomarkers, which give rise to a better understanding and monitoring of disease progression in chronic wounds.

Topics: Aged; Annexins; Biomarkers; Calgranulin B; Chronic Disease; Electrophoresis, Polyacrylamide Gel; Extracellular Matrix Proteins; Exudates and Transudates; Humans; Immunohistochemistry; Inflammation; Lactoferrin; Leg Ulcer; Middle Aged; Proteome; Proteomics; Reproducibility of Results; Wound Healing

To evaluate the efficacy of bovine lactoferrin (BLf), recombinant human lactoferrin (rHLf) and desferrioxamine against Helicobacter pylori in vitro and in mice and also to determine whether BLf or rHLf alter gastric inflammation.. In vitro: Broth dilution susceptibility tests were performed using different concentrations of desferrioxamine, BLf and rHLf. Murine trials: In the prevention trial, C57BL/6 female mice were treated with BLf or rHLF, and then infected with the SS1 strain of H. pylori. In the treatment trial, mice were gavaged with either BLf, rHLf or desferrioxamine. In addition, gastric myeloperoxidase activity (MPO) was measured to assess gastric inflammation. Desferoxamine was found to have a direct bactericidal effect, while BLf and rHLf only partially suppressed H. pylori growth in vitro. However, in both prevention and treatment trials all three forms of treatment failed to reduce H. pylori load in mice. Gastric MPO activity and H. pylori load were noted to be higher with lactoferrin treatments.. Our study does not support the use of BLf or rHLF in the treatment of human H. pylori infection. Interestingly, H. pylori growth and gastric inflammation appear to be enhanced by lactoferrin treatment.. The mouse model is ideal for testing novel H. pylori eradicating agents.

Topics: Animals; Anti-Bacterial Agents; Deferoxamine; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Lactoferrin; Mice; Treatment Outcome

Corpora amylacea (CA) are a frequent microscopic finding in radical prostatectomy specimens from men undergoing treatment for prostate cancer. Although often observed histologically to be associated with inflammation, the contribution of CA to prostatitis-related symptoms of unknown etiology or to prostate carcinogenesis remains unclear. Prostatic calculi (PC), which potentially represent calcified forms of CA, are less common but can cause urological disease including urinary retention and prostatitis. We conducted a comprehensive compositional analysis of CA/PC to gain insight into their biogenesis. Infrared spectroscopy analysis of calculi collected from 23 patients confirmed a prevalence of calcium phosphate in the form of hydroxyapatite. This result sets PC apart from most urinary stones, which largely are composed of calcium oxalate. Tandem mass spectrometry-based proteomic analysis of CA/PC revealed that lactoferrin is the predominant protein component, a result that was confirmed by Western blot analysis. Other proteins identified, including calprotectin, myeloperoxidase, and alpha-defensins, are proteins contained in neutrophil granules. Immunohistochemistry (IHC) suggested the source of lactoferrin to be prostate-infiltrating neutrophils as well as inflamed prostate epithelium; however, IHC for calprotectin suggested prostate-infiltrating neutrophils as a major source of the protein, because it was absent from other prostate compartments. This study represents a definitive analysis of the protein composition of prostatic CA and calculi and suggests that acute inflammation has a role in their biogenesis--an intriguing finding, given the prevalence of CA in prostatectomy specimens and the hypothesized role for inflammation in prostate carcinogenesis.

Topics: Acute-Phase Proteins; Calcium Phosphates; Durapatite; Humans; Inflammation; Lactoferrin; Male; Prostatic Diseases; Prostatic Neoplasms; Tandem Mass Spectrometry

The study aimed to describe the patterns and density of early tracheal colonization among intubated patients and to correlate colonization status with levels of antimicrobial peptides and inflammatory cytokines.. The was a prospective cohort study.. The study was conducted in medical and cardiovascular intensive care units of a tertiary referral hospital.. Seventy-four adult patients admitted between March 2003 and May 2006 were recruited for the study.. Tracheal aspirates were collected daily for the first 4 days of intubation using standardized, sterile technique and sent for quantitative culture and cytokines, lactoferrin and lysozyme measurements.. The mean acute physiology and chronic health evaluation (APACHE II) score in this cohort was 24 +/- 7. Proportion of subjects colonized by any microorganism increased over the first 4 days of intubation (47%, 60%, 70%, 70%, P = .08), but density of colonization for bacteria or yeast did not change significantly. No known risk factors predicted tracheal colonization on day 1 of intubation. Several patterns of colonization were observed (persistent, transient, new colonization, and clearance of initial colonization).The most common organisms cultured were Candida albicans and coagulase-negative Staphylococcus. Levels of cytokines, lactoferrin, or lysozyme did not change over time and were not correlated with tracheal colonization status. Four subjects (6%) had ventilator-associated pneumonia.. The density of tracheal colonization did not change significantly over the first 4 days of intubation in medical intensive care unit patients. There was no correlation between tracheal colonization and the levels of antimicrobial peptides or cytokines. Several different patterns of colonization may have to be considered while planning interventions to reduce airway colonization.

Topics: Adult; APACHE; Candidiasis; Case-Control Studies; Colony Count, Microbial; Cross Infection; Cytokines; Female; Humans; Inflammation; Intensive Care Units; Intubation, Intratracheal; Lactoferrin; Logistic Models; Male; Middle Aged; Multivariate Analysis; Muramidase; Pneumonia, Ventilator-Associated; Prospective Studies; Respiration, Artificial; Respiratory Mucosa; Risk Factors; Staphylococcal Infections; Statistics, Nonparametric; Suction; Time Factors; Trachea

Topics: Animals; Carrier Proteins; Cytokines; Graft vs Host Disease; Humans; Immunotherapy; Inflammation; Lactoferrin; Neoplasms; Neovascularization, Pathologic; Proteasome Endopeptidase Complex; RNA-Binding Proteins

Lactoferrin is an innate immune system protein with multiple beneficial health activities.. To gain insight in the interaction between innate immune system and metabolic disturbances (obesity and insulin resistance), we investigated the relationship between circulating lactoferrin and chronic inflammation-associated insulin resistance according glucose tolerance status in Caucasian population.. Circulating nonstressed lactoferrin (ELISA), metabolic variables, and inflammatory markers were measured in 229 men, 94 with normal (NGT) and 135 with altered glucose tolerance (AGT). Lactoferrin secretion by neutrophil was investigated in whole-blood culture (four young NGT subjects, four older NGT subjects, and four patients with type 2 diabetes) under microbial lipopolysaccharide (LPS) with IL-6 and rosiglitazone treatment. We also tested the lactoferrin action in THP-1 cells under LPS stimulus.. Circulating lactoferrin was significantly decreased in patients with AGT (431.5 +/- 187.5 vs. 493.5 +/- 238.9 ng/ml, P = 0.02). In addition, circulating lactoferrin was negatively associated with hyperglycemia and obesity measures and positively with insulin sensitivity. Lactoferrin was negatively related to inflammatory markers, especially in AGT subjects. In ex vivo experiments, we found a significant decrease in LPS-induced lactoferrin release from neutrophils in subjects with type 2 diabetes. IL-6 coincubation decreased LPS-induced lactoferrin release in NGT subjects (P < 0.001). Finally, rosiglitazone treatment led to increased lactoferrin secretion (398 +/- 193 vs. 280.1 +/- 104.9 ng/ml, P < 0.0001). Lactoferrin decreased nuclear factor-kappabeta activation and IL-6, IL-8, and macrophage chemoattractant protein-1 expression under LPS challenge.. Decreased circulating lactoferrin levels may play a role in chronic low level inflammation-associated insulin resistance.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Chemokine CCL2; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Interleukin-6; Interleukin-8; Lactoferrin; Linear Models; Lipopolysaccharides; Male; Middle Aged; Neutrophils; White People

Topics: Anti-Bacterial Agents; Aza Compounds; Clostridioides difficile; Clostridium Infections; Drug Resistance, Bacterial; Feces; Fluoroquinolones; Humans; Inflammation; Intestines; Lactoferrin; Microbial Sensitivity Tests; Moxifloxacin; Quinolines

We have recently shown that resistin is a key mediator of arthritis accumulating in the inflamed joints and exerting its pro-inflammatory properties independently of TNFalpha. Here we evaluate neutrophils as a cellular source of resistin. Human neutrophils were subjected to subcellular fractionation where the presence of resistin was assessed using western blot, ELISA, and mass spectrometry. Presence of resistin on the neutrophil surface was visualized by flow cytometry. More than 95% of the neutrophils in circulation and in synovial fluid express resistin on their surface. Stimulation of mature neutrophils with fMLF induced release of resistin into supernatants and increased expression of resistin on the surface. Resistin is mobilized simultaneously with lactoferrin, a protein found in specific granules, and with granule-stored CR3/CD11b. Subcellular fractionation of human neutrophils demonstrated the presence of resistin in azurophilic and in specific granules. Here we show that neutrophils have two pools of resistin, the major one exists in specific granules, and the second on their cell membrane. Release of resistin from the neutrophil granules probably serves the main source of resistin at the site of inflammation.

Topics: Adult; Aged; Arthritis; CD11b Antigen; Cell Membrane; Female; Gene Expression Regulation; Humans; Inflammation; Joints; Lactoferrin; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Resistin; Secretory Vesicles

The aim of this work was to evaluate the neutrophil activation state in chronic kidney disease (CKD) patients under hemodialysis, and its linkage with resistance to recombinant human erythropoietin (rhEPO) therapy.. We studied 63 CKD patients under hemodialysis and rhEPO treatment (32 responders and 31 non-responders to rhEPO therapy). In 20 of the CKD patients (10 responders and 10 non-responders to rhEPO therapy), blood samples were also collected immediately after dialysis. Twenty-six healthy volunteers were included in a control group. Hemoglobin levels, total and differential leukocyte counts, and circulating levels of C-reactive protein (CRP), elastase and lactoferrin were measured in all patients and controls.. Compared with controls, CKD patients presented with significantly higher CRP, neutrophil and elastase levels. When we compared the 2 groups of patients, we found that non-responders presented statistically significantly higher elastase plasma levels. A positive significant correlation was found between elastase levels and weekly rhEPO dose and CRP serum levels. After the hemodialysis procedure, a statistically significant rise in elastase, lactoferrin and, elastase/neutrophil and lactoferrin/neutrophil ratios were found.. Our data show that CKD patients under hemodialysis present higher elastase levels (particularly in non-responding patients), which could be related to the rise in neutrophils, and to be part of the enhanced inflammatory process found in these patients.

Topics: Aged; C-Reactive Protein; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Lactoferrin; Lymphocyte Activation; Male; Middle Aged; Models, Statistical; Neutrophils; Pancreatic Elastase; Recombinant Proteins; Renal Dialysis

Ruling out somatic bowel disease, such as inflammatory bowel disease (IBD), is an important goal in the management of abdominal complaints. Endoscopy is commonly used but is invasive and expensive. Mucosal inflammation in IBD can be detected through fecal biomarkers, though the present enzyme-linked immunoabsorbent assay (ELISA) tests require laboratory facilities. We validated the diagnostic performance of two new fecal rapid tests (FRTs) for the detection of calprotectin and lactoferrin and assessed their potential to differentiate IBD from irritable bowel syndrome (IBS).. The calprotectin and lactoferrin FRTs and ELISA tests were performed on the fecal samples of 114 patients referred for endoscopy, 80% of whom had IBS and 20% IBD, and validated against the endoscopic diagnosis.. The sensitivity and negative predictive value of the calprotectin FRT were both 100%, whereas they were 78% and 95%, respectively, for the lactoferrin FRT. The specificity and positive predictive value were slightly higher for the lactoferrin FRT. Both FRTs had similar diagnostic accuracy as the corresponding ELISA tests.. The calprotectin and lactoferrin rapid tests are as good as the ELISA tests in detecting colonic inflammation. Given their simple use, FRTs can support the non-invasive exclusion of IBD, notably in primary care.

Topics: Aged; Colon; Diagnosis, Differential; Endoscopy, Gastrointestinal; Enzyme-Linked Immunosorbent Assay; Feces; Female; Humans; Inflammation; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Lactoferrin; Leukocyte L1 Antigen Complex; Male; Middle Aged; Reproducibility of Results; Sensitivity and Specificity; Time Factors

Levels of lactoferrin (LF), antithrombin-III (AT-III) and beta2-macroglobulin (MG) in blood of patients with rheumatoid arthritis (RA), reactive arthritis (ReA) and systemic lupus erythematosus (SLE) were examined for assessment their importance in differential diagnostics of the diseases. It was shown that on the average, LF and AT-III levels were increased at RA, while MG level was practically unchanged. At the same time LF level was stable high regardless of RA activity and duration degree, but its concentration was significantly increased also in ReA patients (33% patients). AT-III, on the contrary, depended on process activity and duration, was more specific to RA, than LF, but its sensitivity at RA was not enough high (from 25 to 44% patients with increased levels subject to disease duration and activity). Coefficient LFE/AT-III, obtained by multiplication of these proteins concentration, had the greatest diagnostic value. Its sensitivity at RA is on the average 85%, and specificity at differential diagnostics of RA--80% vs. ReA and 92% vs. SLE. We consider that coefficient LFbetaAT-III can be used as an additional criterion at differential diagnostics at RA early stages, while other specific antibodies cannot be detected yet.

Topics: Acute-Phase Proteins; Antithrombin III; Arthritis, Rheumatoid; Biomarkers; Diagnosis, Differential; Female; Humans; Immunoenzyme Techniques; Inflammation; Lactoferrin; Macroglobulins; Male; Middle Aged; Prognosis; Prohibitins

Several inflammatory biomarkers are linked to cardiovascular risk. In order to investigate their coexistence and relative responses, several established and two novel markers (lactoferrin and the terminal complement complex), representing infection and central components of inflammation, were measured simultaneously in patients undergoing first-time coronary angiography.. Blood samples from patients with (n=131) or without (n=103) significant coronary artery stenosis were analyzed for plasma markers representing endothelium, platelets, neutrophils, monocytes, and complement, C-reactive protein, and antibodies against the infectious agents Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus. In multivariate logistic regression analysis, hypercholesterolemia (p<0.001), increased concentrations of the neutrophil activation marker lactoferrin (p<0.001) and the monocyte activation marker neopterin (p=0.012), lower concentrations of the terminal complement complex (p<0.001), and antibodies against C. pneumoniae (p=0.023) were variables linked to coronary artery stenosis. In univariate analysis additional relationships were found to current smoking (p<0.001), increased plasma concentrations of vascular cell adhesion molecule-1 (p=0.015), E-selectin (p<0.01), myeloperoxidase (p=0.051) and endothelin-1 (p=0.053), as well as diabetes (p=0.039).. Activation of multiple inflammatory pathways and C. pneumoniae infection may influence the inflammatory response in atherosclerosis. These pilot data provide an indication of the relative usefulness of various inflammatory biomarkers, indicating that the novel markers lactoferrin and the terminal complement complex warrant further investigation.

Topics: Analysis of Variance; C-Reactive Protein; Chi-Square Distribution; Complement Membrane Attack Complex; Coronary Angiography; Coronary Artery Disease; E-Selectin; Endothelin-1; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lactoferrin; Logistic Models; Male; Middle Aged; Neopterin; Peroxidase; Risk Factors; Vascular Cell Adhesion Molecule-1

When lactoferrin (LF) and myeloperoxidase (MPO) are added to ceruloplasmin (CP), a CP-LF-MPO triple complex forms. The complex is formed under physiological conditions, but also in the course of SDS-free PAGE. Polyclonal antibodies to both LF and MPO displace the respective proteins from the CP-LF-MPO complex. Similar replacement is performed by a PACAP38 fragment (amino acids 29-38) and protamine that bind to CP. Interaction of LF and MPO with CP-Sepharose is blocked at ionic strength above 0.3 M NaCl and at pH below 4.1 (LF) and 3.9 (MPO). Two peptides (amino acids 50-109 and 929-1012) were isolated by affinity chromatography from a preparation of CP after its spontaneous proteolytic cleavage. These peptides are able to displace CP from its complexes with LF and MPO. Both human and canine MPO could form a complex when mixed with CP from seven mammalian species. Upon intravenous injection of human MPO into rats, the rat CP-human MPO complex could be detected in plasma. Patients with inflammation were examined and CP-LF, CP-MPO, and CP-LF-MPO complexes were revealed in 80 samples of blood serum and in nine exudates from purulent foci. These complexes were also found in 45 samples of serum and pleural fluid obtained from patients with pleurisies of various etiology.

Topics: Amino Acid Sequence; Animals; Ceruloplasmin; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Female; Humans; Inflammation; Lactoferrin; Male; Models, Molecular; Peptide Fragments; Peroxidase; Rabbits; Rats

There is a growing awareness of the interaction of food constituents with the immune system. The present study aims to evaluate the anti-inflammatory effects of two of these nutritional components (glycine and bovine-lactoferrin (b-LF)) using two different mouse models. In a zymosan-induced ear-skin inflammation model both components decreased the inflammatory response locally (ear swelling and inflammatory cytokine concentration in the ears) and systemically (number of TNF-alpha producing spleen cells). Glycine effects (20, 50 or 100 mg/mouse/day) were concentration dependent. B-LF (0.1 or 1 mg/mouse/day) inhibited the inflammatory response although higher doses (5 and 25 mg/mouse/day) were not effective. A combination of b-LF 0.1 mg/mouse/day and glycine 20 or 50 mg/mouse/day counteracted the zymosan-induced ear swelling synergistically and enhanced the decrease in the number of TNF-alpha producing spleen cells of the individual components. In a zymosan-induced acute arthritis model glycine (50 mg/mouse/day) inhibited joint swelling, inflammatory cell infiltration and cartilage proteoglycan depletion. A b-LF dose of 5 mg/mouse/day reduced the zymosan-induced joint swelling without modulating inflammatory cell infiltration and cartilage proteoglycan depletion. The present study indicates that the anti-inflammatory effects of glycine are independent of the used models. B-LF displays a reversed concentration dependency and the activity is model dependent. A combination of glycine and lactoferrin demonstrated a synergistic anti-inflammatory effect on zymosan-induced skin inflammation and an enhanced decrease in the number of TNF-alpha producing spleen cells compared to the effect of the single components. Therefore, this nutritional concept might be a new option for the treatment of chronic inflammatory diseases.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Synergism; Glycine; Inflammation; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Proteoglycans; Tumor Necrosis Factor-alpha; Zymosan

The intestinal immune and inflammatory responses of Norovirus (NoV) are poorly defined. The objective of this study was to investigate fecal cytokine and lactoferrin profiles in response to NoV gastroenteritis in travelers. Both fecal cytokines and fecal lactoferrin were measured for NoV-associated diarrhea (N = 7), mixed infection of NoV and enterotoxigenic E. coli (ETEC)-associated diarrhea (N = 10) and in pathogen-negative diarrhea cases (N = 19). Both IL-2 and IFN-gamma were significantly increased in NoV-associated diarrhea specimens, suggesting a predominant Th1 immune response to NoV infection in the gut. When a mixed infection of NoV and ETEC occurred, a combined Th1/Th2 response was observed suggesting a dual immune response secondary to infection by both pathogens. Intestinal inflammation associated with increased fecal lactoferrin, important in bacterial enteric infection, was not found in NoV-associated gastroenteritis.

Topics: Adult; Biomarkers; Caliciviridae Infections; Cytokines; Diarrhea; Feces; Humans; Inflammation; Intestinal Mucosa; Lactoferrin; Middle Aged; Norovirus; Travel

The effect of somatic cell count (SCC) and milk fraction on milk composition, distribution of cell populations, and mRNA expression of various inflammatory parameters was studied. Therefore, quarter milk samples were defined as cisternal (C), first 400 g of alveolar (A1), and remaining alveolar milk (A2) during the course of milking. Quarters were assigned to 4 groups according to their total SCC: 1) <12 x 10(3)/mL, 2) 12 to 100 x 10(3)/mL, 3) 100 to 350 x 10(3)/mL, and 4) >350 x 10(3)/mL. Milk constituents of interest were SCC, fat, protein, lactose sodium, and chloride ions as well as electrical conductivity. Cell populations were classified into lymphocytes, macrophages, and neutrophils (PMN). The mRNA expression of the inflammatory factors tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, lactoferrin, and lysozyme was measured via real-time, quantitative reverse transcription PCR. Somatic cell count decreased from highest levels in C to lowest levels in A1 and increased thereafter to A2 in all groups. Fat content increased from C to A2 and with increasing SCC level. Lactose decreased with increasing SCC level but remained unchanged during milking. Concentrations of sodium and chloride, and electrical conductivity increased with increasing SCC but were higher in C than in A1 and A2. Protein was not affected by milk fraction or SCC level. The distribution of leukocytes was dramatically influenced by milk fraction and SCC. Lymphocytes were the dominating cell population in group 1, but the proportion of lymphocytes was low in groups 2, 3, and 4. Macrophage proportion was highest in group 2 and decreased in groups 3 and 4, whereas that of PMN increased from group 2 to 4. The content of macrophages decreased during milking in all SCC groups whereas that of PMN increased. The proportion of lymphocytes was not affected by milk fraction. The mRNA expression of all inflammatory factors showed an increase with increasing SCC but minor changes occurred during milking. In conclusion, milk fraction and SCC level have a crucial influence on the distribution of leukocyte populations and several milk constituents. The surprisingly high content of lymphocytes and concomitantly low mRNA expression of inflammatory factors in quarters with SCC <12 x 10(3)/mL indicates a different and possibly reduced readiness of the immune system to respond to invading pathogens.

Topics: Animals; Cattle; Cattle Diseases; Cell Count; Cyclooxygenase 2; Female; Inflammation; Interleukin-1; Lactoferrin; Leukocyte Count; Lymphocyte Count; Macrophages; Milk; Muramidase; Neutrophils; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

In recent years, Lf has gained increasing interest as a result of its protective effects against a variety of diseases. While iron binding and interactions with mammalian receptors and microbial components are the best described mechanisms of action, recent studies have provided evidence that Lf properties may be related to immunoregulatory effects on Th1/Th2 cell activities. In vitro and in vivo experiments show that Lf is able to stimulate the differentiation of T cells from their immature precursors through the induction of the CD4 antigen. Studies performed under nonpathogenic conditions have shown distinct results with regard to the ability of Lf to support the proliferation and differentiation of Th cells into the Th1 or the Th2 phenotype. In addition, Lf plays different roles in diseases by affecting the Th1/Th2 cytokine balance in a manner dependent on the host's immune status. Thus, Lf could cause a Th1 polarization in diseases in which the ability to control infection or tumor relies on a strong Th1 response. Lf may also reduce the Th1 component to limit excessive inflammatory responses. Finally, Lf may provide protection against Th1- or Th2-induced diseases, such as autoimmune or allergic diseases, through correction of the Th1/Th2 imbalance.

Topics: Administration, Oral; Animals; Antibodies; Cell Differentiation; Cell Proliferation; Communicable Diseases; Cytokines; Inflammation; Lactoferrin; Mice; Mice, Inbred C57BL; Models, Biological; Th1 Cells; Th2 Cells; Toxoplasma

PEP1261, a tetrapeptide derivative used in this study, corresponds to residues 39-42 of human lactoferrin. The parent protein lactoferrin is known to exhibit antinociceptive activity and it regulates many aspects of inflammation. This study is aimed to evaluate the antinociceptive and antipyretic activities of PEP1261 in rats. PEP1261 exhibits a significant dose dependent antinociceptive activity with optimal effect at 40 mg/kg body weight (b.w.) (i.p.) in both tail-flick model and acetic acid induced writhing in rats. PEP1261 at the doses of 20 and 40 mg/kg b.w. (i.p.) is also observed to exhibit notable antipyretic effect in lipopolysaccharide-induced pyrexia in rats. In conclusion, the results suggest that PEP1261 possesses antinociceptive and antipyretic activities better than the control peptide KRDS.

Topics: Amino Acid Sequence; Analgesics; Analgesics, Non-Narcotic; Animals; Female; Inflammation; Lactoferrin; Oligopeptides; Pain; Rats; Rats, Wistar

Lactoferrin (LF) plays various anti-inflammatory roles in inflammation experimentally induced by lipopolysaccharides (LPS). But the effects of LF on albumin extravasation and neutrophilia have not been elucidated. We aimed to study the effects of LF on albumin extravasation, neutrophilia and/or on other symptoms in inflammation caused by LPS in rats. Human lactoferrin (hLF) was injected (10 mg/100 mL in PBS) 18 h, or 15 min prior to, or 60 min after intraperitoneal injection of LPS in 13 days old Sprague Dawley rats. Prophylactic injection of hLF significantly ameliorated albumin extravasation in ascitic fluid at 5 h and neutrophilia in the blood at 24 h after LPS injection, but the after-injection of hLF did not. Interestingly, an injection of rat anti-TNFalpha IgG 15 min prior to LPS injection did not ameliorate albumin extravasation. Prophylactic injection of hLF significantly ameliorated other symptoms like mortality, and the decrease of phagocytotic activity of peritoneal polymorpho-nuclear leukocytes (PMNL), but did not ameliorate the decrease of platelets in the plasma. These findings suggest that hLF may be available as a medical treatment prior to surgery for prophylaxis of side effects like albumin extravasation or neutrophilia.

Topics: Albumins; Animals; Animals, Newborn; Ascites; Cattle; Humans; Inflammation; Injections, Intraperitoneal; Lactoferrin; Lipopolysaccharides; Neutrophils; Phagocytosis; Rats; Rats, Sprague-Dawley

Lactoferrin (LF) is a ubiquitous protein which exists in milk, plasma, synovial fluids, cerebrospinal fluid and other biological fluids. LF is also well known as a natural immunomodulator. Recently, we found that bovine milk-derived LF (BLF) produced micro-opioid receptor-mediated analgesia. In this study, we examined whether oral administration of BLF causes anti-nociceptive and anti-inflammatory effects, and also whether it modulates LPS-induced TNF-alpha and IL-10 production in rat model of rheumatoid arthritis (RA), rat adjuvant arthritis. BLF was administrated once daily, starting 3 hr before (preventive experiment) or 19 days after (therapeutic experiment) adjuvant injection. In both experiments, BLF suppressed the development of arthritis and the hyperalgesia in the adjuvant-injected paw. The single-administered BLF produced a dose-dependent analgesia, which was reversed by naloxone, in the adjuvant arthritis rats. Both repeated and single administration of BLF suppressed TNF-alpha production and increased IL-10 production in the LPS-stimulated adjuvant arthritis rats. These results suggest that orally administered BLF has both preventive and therapeutic effects on the development of adjuvant-induced inflammation and pain. Moreover, the immunomodulatory properties of BLF, such as down-regulation of TNF-alpha and up-regulation of IL-10, could be beneficial in the treatment of RA. Thus, we concluded that LF can be safely used as a natural drug for RA patients suffering from joint pain.

Topics: Administration, Oral; Analysis of Variance; Animals; Arthritis, Experimental; Disease Models, Animal; Inflammation; Interleukin-10; Lactoferrin; Male; Naloxone; Pain; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Though lactoferrin (LF) is a glycoprotein that is involved in immunomodulation, its action mechanism has not been fully elucidated. Previous studies have suggested that lipopolysaccharide (LPS) activity is inhibited by direct binding between LPS and LF. However, here we show that when LPS and purified LF was mixed, and formed a complex (termed as LF-LPS), it was found to induce production of inflammatory mediators in macrophages to some extent, rather than inhibit LPS activity. Moreover, when macrophages were pretreated with LF-LPS, cells were rendered a tolerant state to LPS challenge. These macrophage-activating effects were mediated by Toll-like receptor 4 (TLR4)-NF-kappaB pathway. Comparative studies with C3H/HeN and C3H/HeJ mice demonstrated the strong dependency of the LF-LPS signal on TLR4. These findings suggest that the immunomodulatory properties of LF could be due, in part, to LPS binding.

Topics: Acute-Phase Proteins; Animals; Blotting, Western; Carrier Proteins; Cells, Cultured; Electrophoretic Mobility Shift Assay; Immunoassay; Inflammation; Lactoferrin; Lipopolysaccharides; Macrophage Activation; Membrane Glycoproteins; Mice; Mice, Inbred C3H; NF-kappa B; Nitrites; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha

The host inflammatory response and innate immunity play a complex role in respiratory diseases.. We evaluated the levels of inflammatory mediators and antibacterial proteins in children who required bronchoscopy and bronchoalveolar lavage fluid (BALF) for clinical indications such as chronic tracheostomy (n=15) and chronic suppurative lung disease (n=8).. Our results suggested the presence of interleukin-1beta (IL-1beta) and IL-8 as major inflammatory mediators in BALF samples. The level of the antibacterial protein sIgA was higher than lactoferrin and lysozyme. BALF IL-8 levels significantly correlated with the presence of IL-1beta, IL-6, IL-10, IL-16, sIgA and lysozyme. BALF IL-8 levels did not correlate with the levels of immunomodulatory and anti-inflammatory clara cell 10 kDa protein (CC10) or lactoferrin.. This study suggests that patients with high levels of BALF IL-8 could potentially have high levels of IL-6, IL-10, IL-16, lysozyme and sIgA. Evaluating the inflammatory mediators (IL-8) in relation to other BALF protein components provides insight into understanding the role of inflammatory mediators in the regulation of host defense and the response to lung inflammation and injury.

Topics: Biomarkers; Bronchiolitis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Child; Humans; Immunity, Innate; Inflammation; Interleukin-1; Interleukin-8; Lactoferrin; Respiration Disorders; Uteroglobin

Because acute bacterial gastroenteritis is often inflammatory, rapid stool assays that detect intestinal inflammation might be used to distinguish between bacterial and nonbacterial gastroenteritis. We performed meta-analyses to determine the discriminatory power, in developed and in resource-poor countries, of rapid stool assays that test for lactoferrin, fecal leukocytes, fecal erythrocytes, and occult blood. In developed countries, the area under the summary receiver operating characteristic curve (AUC/SROC) was 0.89 for fecal leukocytes and 0.81 for occult blood. In resource-poor countries, the AUC/SROC was 0.79 for lactoferrin, 0.72 for fecal leukocytes, 0.63 for occult blood, and 0.61 for fecal erythrocytes. In developed countries, positive and negative likelihood ratios (LR+ and LR-, respectively) for fecal leukocytes were 4.56 and 0.32 when a threshold of >5 cells/high-power field was used, compared with 2.94 and 0.6 in resource-poor countries; for lactoferrin, LR+ was 1.34 and LR- was 0.17 in resource-poor countries when the threshold was an agglutination rating of "+" and a dilution of 1:50. In developing countries, rapid stool assays performed poorly, whereas in developed countries, tests for fecal leukocytes, lactoferrin, and occult blood were moderately useful and could identify patients who were more likely to benefit from empirical antibiotic therapy.

Topics: Developed Countries; Developing Countries; Erythrocytes; Feces; Gastroenteritis; Health Resources; Humans; Inflammation; Lactoferrin; Leukocytes; Occult Blood; Retrospective Studies

Shigella species cause bacillary dysentery in humans by invasion, intracellular multiplication, spread to adjacent cells, and induction of brisk inflammatory responses in the intestinal epithelium. In vitro data suggest that lactoferrin, a glycoprotein present in human mucosal secretions, has a role in protection from bacterial enteric infections. We sought to determine the activity of lactoferrin in vivo, using the concentration present in human colostrum, to investigate its effect on the development of clinical and pathological evidence of inflammation in a rabbit model of enteritis. Lactoferrin protected rabbits infected with Shigella flexneri from developing inflammatory intestinal disease. Typical histological changes in ill animals included villous blunting with sloughing of epithelial cells, submucosal edema, infiltration of leukocytes, venous congestion, and hemorrhage. Lactoferrin at a concentration normally found in human colostrum blocks development of S. flexneri-induced inflammatory enteritis.

Topics: Animals; Disease Models, Animal; Dysentery, Bacillary; Enteritis; Humans; Ileum; Inflammation; Lactoferrin; Rabbits; Shigella flexneri

It has been suggested previously that, in addition to other biological roles, lactoferrin (LF) may display antiinflammatory properties secondary to the regulation of cytokine expression. To explore this concept further, we have here examined in human volunteers the influence of recombinant homologous LF on the migration of epidermal Langerhans cells (LC), a process that is known to be dependent upon the local availability of certain proinflammatory cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). In common with previous studies in mice, it was found that topical administration of LF prior to exposure at the same site to the contact sensitizer diphenylcyclopropenone resulted in a significant reduction of allergen-induced LC migration from the epidermis (measured as a function of the frequency of CD1a+ or HLA-DR+ LC found in epidermal sheets prepared from punch biopsies of the treated skin sites). However, under the same conditions of exposure, LF was unable to influence migration of LC induced by the intradermal administration of TNF-alpha data consistent with the hypothesis that one action of LF in the skin is to regulate the local production of this cytokine. Further support for this hypothesis was derived from experiments conducted with IL-1beta. This cytokine is also able to induce the mobilization of LC following intradermal injection, although in this case, migration is known to be dependent upon the de novo production of TNF-alpha. We observed that prior exposure to LF resulted in a substantial inhibition of IL-1beta-induced LC migration, data again consistent with the regulation of TNF-alpha production by LF. Collectively, these results support the view that LF is able to influence cutaneous immune and inflammatory processes secondary to regulation of the production of TNF-alpha and possibly other cytokines.

Topics: Administration, Topical; Cell Movement; Cytokines; Epidermis; Humans; Inflammation; Lactoferrin; Langerhans Cells; Tumor Necrosis Factor-alpha

The intestinal inflammatory response of traveler's diarrhea acquired in Goa, India, and Guadalajara, Mexico, was studied. Fecal lactoferrin was found in stool samples in which enteroaggregative Escherichia coli (EAEC), enterotoxigenic E. coli, or Salmonella or Shigella species were isolated, with Shigella-positive cases showing the highest level. Samples from cases of Shigella-associated diarrhea had the highest concentrations of fecal cytokines. Travelers to India who had EAEC-associated diarrhea showed elevated levels of interleukin (IL)-8 (median, 341.15 pg/mL) and IL-1beta (median, 749.90 pg/mL). Although 15 travelers to Mexico who had EAEC-associated diarrhea had a median concentration of 0 pg/mL for both IL-8 and IL-1beta, 2 had high levels of IL-8 (1853 and 11,786 pg/mL), and 5 showed elevated levels of IL-1beta (1-1240 pg/mL). Samples from patients in India who had pathogen-negative diarrhea or from patients in Mexico who had asymptomatic EAEC infection were negative for cytokines. Bacterial pathogens causing traveler's diarrhea commonly produce intestinal inflammation, although a subset of patients with EAEC-associated diarrhea fail to develop an inflammatory response.

Topics: Biomarkers; Cytokines; Diarrhea; Escherichia coli; Feces; Humans; Inflammation; Lactoferrin; Salmonella; Shigella; Travel

The aim of this study was to investigate whether technetium-99m labelled fluconazole can distinguish fungal from bacterial infections. Fluconazole was labelled with (99m)Tc and radiochemical analysis showed less than 5% impurities. The labelling solution was injected into animals with experimental infections. For comparison, we used two peptides for infection detection, i.e. UBI 29-41 and hLF 1-11, and human IgG, all labelled with (99m)Tc. Mice were infected with Candida albicans or injected with heat-killed C. albicans or lipopolysaccharides to induce sterile inflammation. Also, mice were infected with Staphylococcus aureus or Klebsiella pneumoniae. Next, accumulation of (99m)Tc-fluconazole and (99m)Tc-labelled peptides/IgG at affected sites was determined scintigraphically. (99m)Tc-fluconazole detected C. albicans infections (T/NT ratio=3.6+/-0.47) without visualising bacterial infections (T/NT ratio=1.3+/-0.04) or sterile inflammatory processes (heat-killed C. albicans: T/NT ratio=1.3+/-0.2; lipopolysaccharide: T/NT ratio=1.4+/-0.1). C. albicans infections were already seen within the first hour after injection of (99m)Tc-fluconazole (T/NT ratio=3.1+/-0.2). A good correlation (R(2)=0.864; P<0.05) between T/NT ratios for this tracer and the number of viable C. albicans was found. Although (99m)Tc-UBI 29-41 and (99m)Tc-hLF 1-11 were able to distinguish C. albicans infections from sterile inflammatory processes in mice, these (99m)Tc-labelled peptides did not distinguish these fungal infections from bacterial infections. It is concluded that (99m)Tc-fluconazole distinguishes infections with C. albicans from bacterial infections and sterile inflammations.

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Candidiasis; Diagnosis, Differential; Fluconazole; Humans; Immunoglobulin G; Inflammation; Lactoferrin; Leukopenia; Lipopolysaccharides; Male; Mice; Myositis; Peptide Fragments; Radionuclide Imaging; Reproducibility of Results; Ribosomal Proteins; Sensitivity and Specificity; Technetium; Thigh; Tissue Distribution

This study compared the possibilities and limitations of 99mTc-labeled synthetic peptides derived from two human antimicrobial peptides, namely, ubiquicidin (UBI) and lactoferrin (hLF), for the scintigraphic detection of bacterial and fungal infections in mice and rabbits. The rationale of our approach was that selected peptides accumulate in infected areas but not in sterile inflammatory lesions, because they bind preferentially to microorganisms. 99mTc-labeled human neutrophil peptides (defensins), ciprofloxacin, and human polyclonal IgG were included as control agents.. 99mTc-labeled peptides and control agents were injected intravenously into animals that had been injected intramuscularly 18 h earlier with multidrug-resistant Staphylococcus aureus, Klebsiella pneumoniae, or fluconazole-resistant Candida albicans. Sterile inflammatory sites were induced by the injection of heat-killed microorganisms or lipopolysaccharide (LPS) into the thigh muscle. Up to 4 h after injection, the accumulation of 99mTc-labeled compounds in the infected/inflamed thigh muscles was determined using scintigraphic techniques and radioactivity counts in dissected tissues.. Scintigraphy revealed that 99mTc-labeled peptides UBI 29-41, UBI 18-35, UBI 31-38, hLF 1-11, and defensins, which showed preferential in vitro binding to microorganisms in a former study, accumulated at a significantly higher rate (P < 0.01) in bacterial and C. albicans infections in mice and rabbits than in inflamed tissues induced by heat-killed microorganisms or by LPS. No significant difference in the accumulation of 99mTc-labeled ciprofloxacin was observed between infected and sterile inflamed thigh muscles in mice.. 99mTc-labeled antimicrobial peptides UBI 29-41, UBI 18-35, UBI 31-38, hLF 1-11, and defensins accumulate significantly in tissues infected with gram-positive and gram-negative bacteria and C. albicans. Significantly lower (P < 0.01) accumulation of these peptides occurs in sterile inflamed tissues. These data indicate that the peptides preferentially tag microorganisms at the site of infection, which is in agreement with their preferential binding to the microorganisms in vitro and in vivo. 99mTc-labeled ciprofloxacin does not distinguish between infections and sterile inflammatory lesions, which implies that its specificity for the detection of bacterial infections is not warranted.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Infections; Candidiasis; Ciprofloxacin; Defensins; Drug Resistance, Multiple; Immunoglobulin G; Inflammation; Klebsiella Infections; Lactoferrin; Male; Mice; Rabbits; Radionuclide Imaging; Radiopharmaceuticals; Ribosomal Proteins; Staphylococcal Infections; Staphylococcus aureus; Technetium

The activation of leukocytes by lipopolysaccharides (LPS), resulting in the oxidative burst, contributes to the pathogenesis of septic shock. The binding of LPS to L-selectin, which was reported as a serum-independent LPS receptor on neutrophils, induces the production of oxygen free radicals. Human lactoferrin (hLf), an anti-inflammatory glycoprotein released from neutrophil granules during infection, binds to LPS. In this study, we investigated the capacity of hLf to inhibit the L-selectin-mediated activation of neutrophils. Our experiments revealed that hLf prevents the binding of LPS to L-selectin in a concentration-dependent manner. Inhibition was maximum (87.7+/-0.5%) at a concentration of 50 microg/ml of hLf. Furthermore, hLf inhibited up to 55.4+/-0.5% of the intracellular hydrogen peroxide production induced by LPS in neutrophils. These findings suggest that the anti-inflammatory properties of hLf are due, at least in part, to their ability to prevent the binding of LPS to neutrophil L-selectin.

Topics: Escherichia coli; Flow Cytometry; Fluorescent Dyes; Humans; Hydrogen Peroxide; Inflammation; L-Selectin; Lactoferrin; Lipopolysaccharides; Neutrophils; Protein Binding; Reactive Oxygen Species

The aim of this study was to select technetium-99m labelled peptides that can discriminate between bacterial infections and sterile inflammations. For this purpose, we first assessed the binding of various 99mTc-labelled natural or synthetic peptides, which are based on the sequence of the human antimicrobial peptide ubiquicidin (UBI) or human lactoferrin (hLF), to bacteria and to leucocytes in vitro. In order to select peptides that preferentially bind to bacteria over host cells, radiolabelled peptides were injected into mice intraperitoneally infected with Klebsiella pneumoniae (K. pneumoniae) and the amount of radioactivity associated with the bacteria and with the leucocytes was quantitated. The next phase focussed on discrimination between bacterial infections and sterile inflammatory processes using 99mTc-labelled peptides in mice intramuscularly infected with various bacteria (e.g. multi-drug-resistant Staphylococcus aureus) and in animals that had been injected with lipopolysaccharides (LPS) of bacterial origin to create a sterile inflammatory process. Also, we studied the distribution of 99mTc-labelled UBI 29-41 and UBI 18-35 in rabbits having an experimental thigh muscle infection with K. pneumoniae and in rabbits injected with LPS. Based on the results of our in vitro and in vivo binding assays, two peptides, i.e. UBI 29-41 and UBI 18-35, were selected as possible candidates for infection imaging. The radiolabelled peptides can detect infections with both gram-positive and gram-negative bacteria in mice as early as 5-30 min after injection, with a target-to-non-target (T/NT) ratio between 2 and 3; maximum T/NT ratios were seen within 1 h after injection. In rabbits, high T/NT ratios (>5) for 99mTc-labelled UBI 29-41 were observed from 1 h after injection. No accumulation of the selected 99mTc-labelled UBI-derived peptides was observed in thighs of mice and rabbits previously injected with LPS. Scintigraphic investigation into the biodistribution of 99mTc-labelled UBI peptides revealed that these peptides were rapidly removed from the circulation by renal excretion. Similar data were observed for 99mTc-labelled defensin 1-3. Our data for 99mTc-labelled hLF and related peptides indicate that these compounds are less favourable for infection detection. Taken together, 99mTc-labelled UBI 18-35 and UBI 29-41 enable discrimination between bacterial infections and sterile inflammatory processes in both mice and rabbits. Based on their characteristics

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Defensins; Diagnosis, Differential; Humans; In Vitro Techniques; Inflammation; Klebsiella Infections; Lactoferrin; Lipopolysaccharides; Male; Mice; Protein Binding; Proteins; Rabbits; Radionuclide Imaging; Ribosomal Proteins; Technetium

Lactoferrin (Lf) is an iron-binding protein involved in host defense against infection and severe inflammation, which accumulates in the brain during neurodegenerative disorders. Prior to determining Lf function in pathological brain tissues, we investigated its transport through the blood-brain barrier (BBB) in inflammatory conditions. For this purpose, we used a reconstituted BBB model consisting of the coculture of bovine brain capillary endothelial cells (BBCECs) and astrocytes in the presence of tumor necrosis factor-alpha (TNF-alpha). As TNF-alpha can be either synthesized by brain glial cells or present in circulating blood, BBCECs were exposed to this cytokine at their luminal or abluminal side. We have been able to demonstrate that in the presence of TNF-alpha, whatever the type of exposure, BBCECs were activated and Lf transport through the activated BBCECs was markedly increased. Lf was recovered intact at the abluminal side of the cells, suggesting that increased Lf accumulation may occur in immune-mediated pathophysiology. This process was transient as 20 h later, cells were in a resting state and Lf transendothelial traffic was back to normal. The enhancement of Lf transcytosis seems not to involve the up-regulation of the Lf receptor but rather an increase in the rate of transendothelial transport.

Topics: Animals; Animals, Newborn; Astrocytes; Biological Transport; Blood-Brain Barrier; Cattle; Coculture Techniques; E-Selectin; Endothelium, Vascular; Inflammation; Intercellular Adhesion Molecule-1; Lactoferrin; Rats; Stimulation, Chemical; Tumor Necrosis Factor-alpha

Enteroaggregative E. coli (EAggEC) are emerging as an important cause of persistent diarrhea, especially in children in the developing world, yet the pathogenesis of EAggEC infection is poorly understood. In an ongoing prospective study of childhood diarrhea in an urban Brazilian slum, EAggEC are the leading cause of persistent diarrhea. Children from this study with EAggEC and persistent diarrhea had significant elevations in fecal lactoferrin, interleukin (IL)-8, and IL-1beta. Moreover, children with EAggEC without diarrhea had elevated fecal lactoferrin and IL-1beta concentrations. The children with EAggEC in their stool had significant growth impairment after their positive culture, regardless of the presence or absence of diarrhea. Finally, 2 EAggEC strains were shown to cause IL-8 release from Caco-2 cells, apparently via a novel heat-stable, high-molecular-weight protein. These findings suggest that EAggEC may contribute to childhood malnutrition, trigger intestinal inflammation in vivo, and induce IL-8 secretion in vitro.

Topics: Brazil; Caco-2 Cells; Case-Control Studies; Cells, Cultured; Child, Preschool; Diarrhea; Escherichia coli; Escherichia coli Infections; Feces; Growth Disorders; Humans; Infant; Infant, Newborn; Inflammation; Interleukin-1; Interleukin-8; Intestines; Lactoferrin; Polymerase Chain Reaction; Prospective Studies; RNA, Messenger

In the process of host defence against microbial challenge, neutrophils release granule contents with the potential side effect of damaging structural tissues. In the junctional epithelium such damage may contribute to the degeneration and renewal of the epithelial cells attached directly to the tooth (DAT cells), and subsequently to periodontal pocket formation. This study reports on lactoferrin, one of the substances released by neutrophils, and its effects on epithelial cell adhesion, growth, DNA synthesis and spreading of cell colonies at concentrations recorded in the crevicular fluid. We show that, in opposition to what has been reported on bacterial cells, lactoferrin has no effect on the DNA synthesis of attached epithelial cells in model systems attempting to simulate the DAT cells in vivo. However, both iron-saturated and unsaturated lactoferrin hampered cell adhesion, growth and spreading of cell colonies in a dose-dependent manner. These findings suggest that lactoferrin does not affect epithelial cell proliferation but it may have a role in delaying the repair of the DAT cell population during inflammation by interfering with cell adhesion.

Topics: Adolescent; Animals; Autoradiography; Bacteria; Bromodeoxyuridine; Cell Adhesion; Cell Death; Cell Degranulation; Cell Division; Cell Line; Cell Movement; Cells, Cultured; Child; Cytoplasmic Granules; DNA; Dose-Response Relationship, Drug; Epithelial Attachment; Epithelial Cells; Gingiva; Gingival Crevicular Fluid; Humans; Indicators and Reagents; Inflammation; Iron; Lactoferrin; Mouth Mucosa; Neutrophils; Periodontal Ligament; Periodontal Pocket; Radiopharmaceuticals; Skin; Swine; Thymidine; Tritium

The aim of this study was to investigate an effect of oral treatment of rats with bovine lactoferrin (BLF) on carrageenan-induced inflammation. Rats were given 5 oral doses of BLF (10 mg each) on alternate days and 24 h after the last dose a carrageenan inflammation was induced in the hind foot. Control rats were given 0.9% natrium chloride (NaCl) or bovine serum albumin (BSA). The magnitude of the reaction was measured after 2 h (optimal response) and expressed as an increase of the foot pad thickness in milimeters. The evaluation of BLF effects on carrageenan reaction was supplemented by determination of the ability of spleen cell cultures to produce interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) upon lipopolysaccharide (LPS) induction using bioassays. The results revealed an inhibition of the carrageenan-induced inflammation in BLF-treated rats by 50 and 40% as compared to NaCl and BSA control groups, respectively. The inhibition was also associated with a substantial decrease in the ability of splenocytes to produce IL-6 in BLF-treated rats (94 and 83% as compared to NaCl- and BSA-treated groups). The LPS-induced TNF-alpha production was also decreased, although to a lesser degree (48 and 35%, respectively). The decreased ability of spleen cells to produce inflammatory cytokines in BLF-treated rats indicates that hyporeactivity of the immune system cells may be the basis for the inhibition of carrageenan-induced inflammation.

Topics: Administration, Oral; Animals; Carrageenan; Cattle; Cytokines; Female; Inflammation; Lactoferrin; Male; Rats; Rats, Wistar

The aim of this study was to determine whether allergic inflammation induces nasal hyperreactivity to bradykinin by enhancing neuronal responsiveness.. We compared the response to localized, unilateral nasal challenge with bradykinin in patients with perennial allergic rhinitis and nonallergic subjects, and in patients with seasonal allergic rhinitis challenged in and out of season. Weights of secretions from each nostril were recorded, and levels of albumin and lactoferrin in secretions recovered from each nostril were assayed. Contralateral administration of atropine (0.32 mg) was used to evaluate the role of cholinergic reflexes in nasal hyperresponsiveness to bradykinin.. In patients with symptomatic allergy, bradykinin induced greater symptom scores than in asymptomatic atopic or nonallergic control subjects. Moreover, bradykinin caused sneezing in a majority of patients with symptomatic allergy but in none of the asymptomatic atopic or nonallergic control subjects. Only patients with symptomatic allergy showed dose-dependent bilateral increases in secretion weights and levels of the serous glandular marker, lactoferrin. In contrast, bradykinin induced similar increases in ipsilateral, but not contralateral, levels of albumin in all patient populations. Atropine inhibited contralateral secretion and lactoferrin production (p < 0.05) in patients with symptomatic allergy.. The induction of sneezing and of atropine-inhibitable contralateral glandular secretion demonstrates that allergic inflammation causes nasal hyperreactivity to bradykinin, at least in part, by enhancing neuronal responsiveness.

Topics: Adult; Albumins; Allergens; Atropine; Bradykinin; Cross-Over Studies; Double-Blind Method; Female; Humans; Hypersensitivity; Immunoglobulin E; Inflammation; Lactoferrin; Male; Muscarinic Antagonists; Nasal Mucosa; Nasal Provocation Tests; Reflex; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Using a lactoferrin latex agglutination assay, we have compared the inflammatory responses to a cholera vaccine candidate, CVD 110, in which all known toxin genes have been deleted or mutated yet still produced significant diarrhea, with a less reactive vaccine strain and wild-type El Tor and 0139 Vibrio cholerae strains. Data suggest that diarrhea due to attenuated and wild-type El Tor V. cholerae, and to a lesser extent 0139 V. cholerae, involves an inflammatory response. Further study is required to further elucidate the mechanism of the process(es) involved.

Topics: Cholera Vaccines; Diarrhea; Humans; Inflammation; Lactoferrin; Neutrophils; Vaccines, Attenuated; Vibrio cholerae

The aggregation of non-serotypable Haemophilus influenzae (NTHI) by whole saliva from patients with chronic obstructive lung disease (COLD) was investigated. Significant differences were observed between salivary aggregating activity of a control and COLD population (P < 0.001). Saliva from patients less prone to acute exacerbations had a greater capacity to aggregate bacteria compared with saliva from patients with a predilection to infection. The mechanism of saliva-mediated aggregation of NTHI was investigated and shown to be related to lysozyme content. Lysozyme activity in saliva was measured by the turbidimetric technique and results showed that patients with chronic bronchitis had increased levels of salivary lysozyme, with a subpopulation within the non-infection-prone group having greater amounts. A significant difference was observed in salivary lysozyme between controls and non-infection-prone (P < 0.005) and infection-prone (P < 0.05) patients, respectively: the non-infection-prone patients having significantly (P < 0.005) more than the infection-prone patients. There was significant correlation (r = 0.742, P < 0.001) between salivary aggregation of NTHI and lysozyme activity. Chromatographically purified human lysozyme had a similar aggregation profile to that of saliva. There was no difference in serum and saliva lactoferrin concentrations between groups, but there was a significant increase (P < 0.05) in serum lysozyme concentration in the non-infection-prone group. This study suggests that the level of salivary lysozyme derived from macrophages may play an important role in determining resistance or susceptibility to acute bronchitis.

Topics: Acute Disease; Adult; Aged; Bronchitis; Chronic Disease; Communicable Diseases; Female; Haemophilus influenzae; Humans; Inflammation; Lactoferrin; Lung Diseases, Obstructive; Macrophages; Male; Middle Aged; Monocytes; Muramidase; Neutrophils; Saliva; Salivation

To test lactoferrin as a marker of neutrophil activation during pregnancy.. Cross-sectional study in normal pregnant (n = 100), nonpregnant (n = 11) and post partum women (n = 30).. Serum or plasma measurements of neutrophils, lactoferrin, vitamin C, vitamin E, lipid peroxide, elastase, C-reactive protein gamma-glutamyltranspeptidase, haptoglobin and osmotic fragility.. During normal pregnancy all markers of neutrophil-activation increase.. Neutrophil-activation compromises the antioxidant defense mechanism during normal pregnancy.

Topics: Adult; Biomarkers; Cell Membrane; Erythrocytes; Female; Hematologic Tests; Humans; Inflammation; Lactoferrin; Leukocyte Count; Lipid Peroxidation; Neutrophil Activation; Oxidation-Reduction; Pancreatic Elastase; Pregnancy; Reference Values; Sensitivity and Specificity

Bovine lactoferrin (BLF) given into mice, sensitized to SRBC, together with the eliciting dose of antigen, inhibits very strongly the DTH reaction measured after 24 h by foot pad swelling. Administration of BLF at 48 or 24 h before eliciting the DTH reaction was not effective, however, BLF suppressed the reaction when given at the peak of the inflammatory process. The effects of BLF were strongest when the protein was injected intravenously. Intraperitoneal or intramuscular administrations of BLF were less inhibitory. In addition, BLF diminishes, although to a much lesser degree, the inflammatory reactions induced by BCG. The inhibitory action of BLF does not involve liver since treatment of mice with galactosamine does not reverse the inhibition. Studies on cytokine production revealed that peritoneal macrophages, derived from mice pretreated with LF, have an increased ability to produce in vitro IL-6 after induction with LPS. In addition, we demonstrated that inhibition of macrophage migration, mediated by migration inhibition factor, is abolished by BLF. Lastly, the inhibitory effect of BLF could not be transferred with serum from donors treated with BLF. In summary, the data reveal the inhibitory properties of LF, administered systematically, in relation to locally induced inflammation.

Topics: Animals; Cattle; Cytotoxicity, Immunologic; Erythrocytes; Female; Guinea Pigs; Hypersensitivity, Delayed; Inflammation; Injections, Intravenous; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Mycobacterium bovis; Sheep

The oviduct provides the environment in which fertilization of the egg and subsequent development of the preimplantation mouse embryo occurs, but little is known about the oviduct's capacity to produce growth factors or cytokines that may influence these preimplantation events. Northern blot analysis and/or immunohistochemistry were employed to examine the expression or cellular distribution, respectively, of the growth factors heparin-binding epidermal-like growth factor (HB-EGF), transforming growth factor (TGF) alpha, epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), TGF beta 1, TGF beta 2, and TGF beta 3; of estrogen-regulated lactoferrin (LF); and of the cytokines interleukin (IL)-1 alpha and IL-1 beta in the mouse oviduct during the preimplantation period (Days 1-4 [Day 1 = vaginal plug]) and 7 days after ovariectomy. The results demonstrated that, except for EGF, each of the growth factors and the LF genes are expressed in the ampulla and isthmus regions of the oviduct throughout the preimplantation period. Prominent immunostaining in secretory epithelial cells was noted for HB-EGF, TGF alpha, IGF-I, TGF beta 1, and TGF beta 2, and LF. Less intense immunostaining in the serosa and/or smooth muscle was also noted for TGF alpha, IGF-I, and TGF beta 1. In contrast, intense immunostaining in smooth muscle was noted for TGF beta 2, and TGF beta 3 was detected exclusively in smooth muscle cells. The abundance of these mRNAs was relatively constant during the preimplantation period, and ovariectomy did not reduce the levels of these mRNAs. In contrast to these growth factors, the cytokine mRNAs examined (IL-1 alpha and IL-1 beta) were at or below the limits of detection under these experimental conditions, and inflammatory leukocytes (LF-immunopositive neutrophils, IL-1 beta-immunopositive monocytes/macrophages, or peroxidase-positive eosinophils) were not detected in the oviduct, but were abundant in the adjacent uterine stroma on Day 1. These studies show that several growth factors are synthesized by the mouse oviduct and suggest that ovarian steroids do not play a major role in modulating expression of these genes in the oviduct during the preimplantation period. Furthermore, unlike the uterus on Day 1, the oviduct does not exhibit an inflammatory response to mating.

Topics: Animals; Blotting, Northern; Embryonic Development; Eosinophils; Epidermal Growth Factor; Fallopian Tubes; Female; Gene Expression; Growth Substances; Inflammation; Insulin-Like Growth Factor I; Interleukin-1; Lactoferrin; Leukocytes; Mice; Monocytes; Neutrophils; Ovariectomy; Pregnancy; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta

Skin test anergy, the failure to produce a delayed type hypersensitivity (DTH) response, is associated with an increase in infection-related complications and death usually due to multiple organ failure (MOF). Refractory intravascular activation of polymorphonuclear neutrophils (PMNs) has been implicated in the development of MOF. We studied 20 critically ill surgical patients with life threatening infections to determine if PMN intravascular activation was present and how this affected essential PMN functions such as exudation. The 11 anergic patients had a more intense inflammatory response to their infection. Plasma lactoferrin was 6.1 +/- 0.3 microgram/ml in anergic patients compared to 3.9 +/- 1.5 in reactive P less than 0.05, accompanied by reduced total primary (3.3 +/- 1.9 vs 4.7 +/- 2.1 micrograms/10(6) PMN P less than 0.01) and secondary (2.8 +/- 0.4 vs 5.0 +/- 0.9 microgram/10(6) PMN P less than 0.01) granule content, respectively. In vitro superoxide production following 100 ng/ml PMA stimulation was 0.44 +/- 0.1 in anergics vs 0.36 +/- 0.1 nmol/microgram PMN protein in reactivities, P less than 0.05. PMN chemotaxis was 8.2 +/- 0.6 PMNs/HPF in anergics compared to 10.2 +/- 1.6 PMNs/HPF in reactives P less than 0.05, accompanied by decreased PMN delivery to skin blister windows (3.2 +/- 1.4 vs 4.5 +/- 1.9 x 10(7) PMN/ml, respectively, P less than 0.05). We conclude that critically ill anergic surgical patients have increased intravascular PMN activation, which may contribute to oxygen-derived tissue damage in the vascular space, as well as a deficient delivery of effector cells in areas of bacterial invasion. This may lead to inability to clear the inflammatory signals which set up the vicious circle of MOF leading to death.

Topics: Cell Adhesion; Cell Degranulation; Chemotaxis, Leukocyte; Exudates and Transudates; Glucuronidase; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Inflammation; Lactoferrin; Macrophage-1 Antigen; Neutrophils; Respiratory Burst; Skin Tests; Superoxides; Surgical Procedures, Operative

"Whole body inflammation" induced by cardiopulmonary bypass may play a role in the pathogenesis of postoperative complications after open-heart surgery. The inflammatory response, in terms of complement activation and release of granular proteins from neutrophil granulocytes, was investigated in six patients undergoing aortocoronary bypass surgery. Complement activation was demonstrated as well as substantially increased plasma levels of lactoferrin and myeloperoxidase--two granulocyte factors. The activation of inflammatory systems probably takes place on the artificial surfaces of the extracorporeal device. The biocompatibility of these components therefore should be further studied.

Topics: Aged; Cardiopulmonary Bypass; Complement C3; Coronary Artery Bypass; Coronary Disease; Humans; Inflammation; Lactoferrin; Male; Middle Aged; Peroxidase

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is a powerful growth and differentiation factor which acts on hematopoietic progenitor cells and also activates differentiated granulocytes and macrophages. This study shows that mouse peritoneal macrophages can be induced to accumulate GM-CSF mRNA and to release GM-CSF by inflammatory agents (lipopolysaccharide, fetal calf serum, thioglycolate broth); phagocytosis; and adherence in the presence of fibronectin. GM-CSF mRNA accumulation, which is totally prevented by the corticosteroid dexamethasone and by interferon-gamma, is not accompanied by changes in the gene's transcriptional level. No interleukin 3 (multi-CSF) mRNA is detectable in induced macrophages. These findings have implications in the understanding of hematopoiesis and of the inflammation and repair process.

Topics: Animals; Cell Differentiation; Dexamethasone; Fibronectins; Hematopoiesis; Inflammation; Interferon-gamma; Interleukin-3; Lactoferrin; Lipopolysaccharides; Macrophages; Mice; Phagocytosis; Protein Processing, Post-Translational; RNA, Messenger; Thioglycolates

Leukocyte aggregation is involved in the generation of vascular damage during various inflammatory conditions. So far, in vitro leukocyte aggregation has been studied by mixing patients' plasma or serum with leukocytes of a normal donor in a platelet aggregometer. We evaluated the leukergy phenomenon, that is, the occurrence of aggregated leukocytes in peripheral blood of patients with inflammatory disorders, as an alternative tool to the former method. Leukocyte aggregation could be induced by zymosan-activated plasma, phorbol myristate acetate, and formyl-methionyl-leucyl-phenylalanine, as well as by the calcium ionophore A23187 in vitro in whole human blood. This aggregation was blocked by various lipoxygenase and cyclooxygenase pathway inhibitors. Leukergy was diagnosed in peripheral blood of patients with inflammatory disorders and was generally not associated with elevated concentrations of immune complexes, lactoferrin, C3a des Arg, or C5a des Arg. To the best of our knowledge, this is the first report on leukocyte aggregation studies performed in whole blood. Such study permits evaluation of the aggregation phenomena of leukocytes in their natural milieu. Furthermore, it is possible with this method to obtain direct visualization of leukocytic aggregates in the peripheral blood of patients. The significance of our results and their possible implications are discussed in light of the pertinent literature.

Topics: Adult; Aged; Antigen-Antibody Complex; Cell Aggregation; Complement C3; Complement C3a; Complement C5; Complement C5a, des-Arginine; Female; Humans; Inflammation; Lactoferrin; Leukocytes; Male; Middle Aged; Tetradecanoylphorbol Acetate; Zymosan

The interrelationships between various components of the non-immune inflammatory response (white cell count, plasma lactoferrin, C-reactive protein, ferritin, iron and iron-binding capacity), were studied serially in a variety of inflammatory conditions including acute lobar pneumonia, active pulmonary tuberculosis, rheumatoid arthritis on gold therapy and sepsis in the face of marrow hypoplasia induced by chemotherapy. Lactoferrin concentrations paralleled the white count in all groups. They were highest in pneumonia and tuberculosis, mildly elevated in rheumatoid arthritis and markedly decreased in neutropenic sepsis. Very high initial lactoferrin concentrations were associated with a poor prognosis in acute pneumonia. C-reactive protein and ferritin concentrations remained elevated through the period of study in acute pneumonia and neutropenic sepsis, while they gradually normalised over weeks in subjects with tuberculosis or rheumatoid arthritis on therapy. In pneumonia and tuberculosis moderate hypoferraemia and a reduced iron-binding capacity were evident. In contrast, a raised percentage saturation was present in neutropenic sepsis, probably related to erythroid marrow suppression. Comparisons between ferritin, lactoferrin and C-reactive protein in the various groups supported the concept that ferritin behaves in part as an acute phase reactant and that hypoferraemia in inflammation is due to deviation of iron into ferritin stores. The suggestion that lactoferrin is responsible for the hypoferraemia and hyperferritinaemia was not supported by the present data. Iron deficiency appeared to limit the hyperferritinaemic response in rheumatoid arthritis, while erythropoietic inhibition by chemotherapy dampened the hypoferraemic response in neutropenic sepsis.

Topics: Arthritis, Rheumatoid; C-Reactive Protein; Ferritins; Humans; Inflammation; Iron; Lactoferrin; Lactoglobulins; Leukocyte Count; Pneumonia; Sepsis; Tuberculosis, Pulmonary

Cell-free, fat-free mammary secretions were tested in vitro for ability to support growth of streptococci associated with mastitis. Secretions were obtained prior to drying off, during the dry period, at calving, and during lactation from four cow treatment groups. Treatment groups were dry cow therapy, dry cow therapy and mammary glands subjected to induced inflammation 7 d post-drying-off, no dry cow therapy and no induced inflammation, no dry cow therapy but mammary glands subjected to induced inflammation. Growth of Streptococcus uberis, Streptococcus faecalis, and Streptococcus agalactiae in secretions from nonlactating glands was unaffected by induced inflammation. Growth of Streptococcus bovis was significantly inhibited in secretion obtained 14 d after induced inflammation. Dry cow therapy had no effect on streptococcal growth in secretion obtained 7 d after therapy. Streptococcal growth was greatest in secretions from involuted glands, and there was little or no evidence for growth inhibitory factors in cell-free, fat-free secretions obtained during the dry period. Milk from lactating glands inhibited streptococcal growth, and the inhibitory factor was presumptively identified as lactoperoxidase. Apolactoferrin, immunoglobulin, or both had little effect on streptococcal growth.

Topics: Animals; Apoproteins; Bacteriological Techniques; Body Fluids; Cattle; Citrates; Citric Acid; Culture Media; Disease Susceptibility; Female; Immunoglobulins; Inflammation; Lactation; Lactoferrin; Mammary Glands, Animal; Mastitis, Bovine; Milk; Novobiocin; Pregnancy; Streptococcal Infections; Streptococcus

Plasma levels of lactoferrin (LF) have been found to be increased in a few patients with cystic fibrosis (CF). This study was aimed at investigating plasma LF levels in children with CF (26 cases) and in controls (C) (19 cases). Plasma LF was measured by a radioimmunoassay method. Plasma LF levels were not significantly different in CF and in C, even though 10 CF patients showed LF levels above the mean + 2 SD value of the controls. Neither the duration of the disease nor the age of the controls was correlated with LF or with the exocrine pancreatic capacity. A significant relationship between the presence of an acute lung inflammation and LF levels was found. This study shows that LF is increased in CF only in the presence of an acute inflammatory state. Further studies are necessary to establish the usefulness of an LF assay as an index of the presence of an acute inflammatory process.

Topics: Adolescent; Child; Child, Preschool; Cystic Fibrosis; Humans; Infant; Inflammation; Lactoferrin; Lactoglobulins; Lung Diseases

35 specimens of human parotid gland and 37 of submandibular gland were transplanted into athymic nude mice. At distinct time intervals, from 1 day to 8 months the transplants were collected and examined. The transplanted glands were studied by light microscopy, immunohistology and autoradiography. The following changes were detectable: acute injury to the xenograft and inflammatory reaction (day 1-7), regeneration of the transplant and the beginning of adaptation to the "mouse milieu" (day 8-30), completion of adaptation (day 30 and later). The presence of the following substances was analysed: amylase, lactoferrin, secretory component, tissue polypeptide antigen (TPA). Amylase was only detected in the early transplants. Lactoferrin was seen only in the small duct system. TPA was present during all transplantation periods and was quantitatively correlated with the 3H thymidine labeling index. From our observations we can say that the salivary glands show two different reacting compartments: a large and a small duct system. The histogenesis of the xenografts, and the relationships of the changes observed to human salivary gland diseases were discussed.

Topics: Amylases; Animals; Autoradiography; Cell Division; Connective Tissue; Epithelium; Female; Histocytochemistry; Humans; Inflammation; Lactoferrin; Mice; Mice, Nude; Mitotic Index; Necrosis; Parotid Gland; Salivary Glands; Secretory Component; Submandibular Gland; Time Factors; Transplantation, Heterologous

The CSF levels of lactoferrin, lysozyme, and beta 2-microglobulin (beta 2 mu) were measured in patients with evident, probable, or possible inflammatory CNS reactions and compared to those found in neurologically apparently healthy patients. Patients with viral CNS infections had significantly raised beta 2 mu and lysozyme levels but normal lactoferrin levels, indicating a local activation of lymphocytes and monocytes but not of granulocytes. Patients with bacterial CNS infections had significantly raised levels of all three cell markers, but the increase of lysozyme and lactoferrin was relatively more pronounced than that of beta 2 mu, indicating that the inflammatory response to bacterial agents is dominated by monocytes and granulocytes. Patients with primary or secondary malignant brain tumors were characterized by a moderate increase of beta 2 mu and a considerable increase in both lysozyme and lactoferrin, i.e., the same protein pattern as observed in bacterial CNS infection. The lysozyme levels were moderately increased in half the patients with benign cerebral tumors while the levels of beta 2 mu and lactoferrin were normal, indicating that benign and malignant brain tumors induce different local inflammatory CNS reactions. Half the patients with pituitary gland adenoma had elevated beta 2 mu and lysozyme levels but normal lactoferrin levels, suggesting that immunological mechanisms are associated with the adenoma development. Patients with MS had moderately but significantly raised CSF levels of beta 2 mu and lysozyme and a third of them also had raised levels of lactoferrin, a protein pattern suggesting a low-active inflammatory process in CNS involving mononuclears and granulocytes. A similar protein pattern was found in Guillain-Barré syndrome. In cerebrosarcoidosis we noted considerably increased lysozyme and beta 2 mu but normal lactoferrin levels, consistent with the idea that the sarcoid granuloma mass is dominated by monocytic inflammatory cells. The data obtained indicate a clinical value of lactoferrin, lysozyme, and beta 2 mu as differential indices of inflammatory cell reactions taking place in various CNS processes.

Topics: Adult; Albumins; Bacterial Infections; beta 2-Microglobulin; Beta-Globulins; Central Nervous System Diseases; Cerebrospinal Fluid Proteins; Female; Humans; Inflammation; Lactoferrin; Lactoglobulins; Male; Muramidase; Virus Diseases

The uptake of 67Ga as citrate, chloride and complexed by carrier-proteins (lactoferrin and transferrin) has been studied in tumor- and inflammatory lesion-bearing rats. Different uptake patterns are shown by tumors and lesions. 67Ga-transferrin complexes are taken up to the highest extent by tumors and inflammatory lesions. The comparative distribution studies using normal animals indicate a systemic increase of 67Ga uptake by tumor- and lesion-bearing animals which might be of importance in explaining the mechanism of 67Ga accumulation. The role of ionic environment changes and radioactivity concentration by isomorphous ionic replacement is discussed.

Topics: Animals; Gallium; Gallium Radioisotopes; Inflammation; Lactoferrin; Lactoglobulins; Male; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Sarcoma, Experimental; Tissue Distribution; Transferrin

The rather narrow variation in the number of mononuclear phagocytes in blood and tissues under steady-state conditions attests to a fine tuning mechanism regulating monocyte production and distribution. Some factors, such as CSF, prostaglandins, and lactoferrin, which are thought on the basis of in vitro findings to control homeostasis of the mononuclear phagocyte system, are reviewed, confirmation of the physiologic role of these factors will require in vivo studies. Under conditions leading to an increased demand for macrophages in tissues, large numbers of monocytes are produced in the bone marrow. Two endogenous factors, i.e. the factor increasing monocytopoiesis (FIM) and the monocyte production inhibitor (MPI), have been found to regulate monocytopoiesis in vivo during an inflammation. FIM occurring in the circulation during the initial phase of the inflammatory reaction is a protein that has no colony-stimulating activity, is cell-line specific, and stimulates the mitotic activity of the promonocytes and probably also the proliferation of the monoblasts. Macrophages produce and secrete FIM. MPI occurs in the circulation during the second phase of an inflammation. Although with the present assays these factors are only demonstrable during inflammation, which indicates that FIM and MPI are regulators of monocytopoiesis under increased demand, their possible role in control of homeostasis under normal steady-state conditions is not yet clear.

Topics: Animals; Bone Marrow Cells; Cell Cycle; Cell Division; Cell Movement; Colony-Stimulating Factors; Dinoprostone; Hematopoietic Stem Cells; Inflammation; Kinetics; Lactoferrin; Mice; Monocytes; Phagocytes; Prostaglandins E; Rabbits

The present study was carried out to compare radiological and physiological changes in sarcoidosis with biochemical markers for inflammatory cell populations. Of 53 patients with sarcoidosis, 28 had respiratory symptoms and 30 past or present bilateral hilar adenopathy without symptoms. A clinical score based on lung function tests and radiological findings correlated well with elevations of lysozyme and beta2-microglobulin in serum, indicating increased inflammatory cell activity in patients with more severe lung affection. A covariation between beta2-microglobulin and lysozyme was found, suggesting concomitant activation of macrophages and lymphocytes in sarcoidosis. Serum levels of lactoferrin were elevated in patients with a disease of short duration but did not correlate with the severity of the lung affection. The closing volume also seems to be abnormal in the early course of the disease, while elevated lysozyme and beta2-microglobulin levels rather seem to reflect the extent of the pulmonary affection.

Topics: Adult; Aged; beta 2-Microglobulin; Female; Humans; Inflammation; Lactoferrin; Lung; Lung Diseases; Male; Middle Aged; Muramidase; Radiography; Respiratory Function Tests; Sarcoidosis

The concentrations of several polymorphonuclear neutrophilic lysosomal constituents were quantitated by immunochemical and enzymatic assays in 28 inflammatory and 9 noninflammatory synovial fluids. The quantities of lactoferrin, myeloperoxidase, and enzymatically determined lysozyme were covariate with the neutrophil count. Enzymatic activities measured with synthetic substrates developed for the assay of chymotryptic-like cationic protein (cathepsin G) and elastase, along with immunochemically determined lysozyme, were independent of the neutrophil count. Although the latter assays were developed and standardized with human neutrophilic lysosomal constituents, they measure different activities in inflammatory synovial effusions. No elastase was detected if elastin was used as the substrate. Regardless of the source of the enzymes, there was a negative correlation between their concentration and the degree of radiographic destruction of the joint from which the fluid was obtained. Lysosomal enzymes in solution in synovial fluid are not likely to be primarily involved in cartilage destruction.

Topics: Cathepsins; Complement C3; Humans; Inflammation; Lactoferrin; Lysosomes; Muramidase; Neutrophils; Pancreatic Elastase; Peroxidase; Synovial Fluid; X-Rays

Lactoferrin (LF), the iron-binding protein of external secretions and neutrophilic polymorphonuclear leukocytes (PMN), was studied in 27 patients during granulocytosis caused by acute inflammation and in disorders without granulocytosis (iron deficiency anemia, iron overload and liver diseases). During granulocytosis the LF concentration of PMN was significantly lower than in controls (p less than 0.001). This difference proved to be related to the number of PMN. A relation between the LF concentration of PMN and iron metabolism could be demonstrated: loss of iron by blood donation is accompanied by a significant decrease in the LF concentration in PMN, whereas iron therapy in patients with iron deficiency anemia is accompanied by a significant increase in the LF concentration in PMN.

Topics: Anemia, Hypochromic; Blood Transfusion; Female; Fluorescent Antibody Technique; Hepatitis; Humans; Immunodiffusion; Inflammation; Iron; Lactoferrin; Lactoglobulins; Leukocytosis; Liver Cirrhosis; Neutrophils

Topics: Animals; Blood Proteins; Gallium; Gallium Radioisotopes; Glycoproteins; Humans; Inflammation; Lactoferrin; Lysosomes; Microsomes; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Protein Binding

The hyposideremia of inflammation was found to be based on a three-step mechanism involving lactoferrin, the iron-binding protein from the specific granules of neutrophilic leukocytes. (a) Lactoferrin is Released from Neutrophils in an Iron-Free Form. When phagocytosis was induced in neutrophils by zymosan or bacteria, lactoferrin was recovered in the incubation medium together with other constituents of the specific granules, such as alkaline phosphatase and lysozyme. Lactoferrin extracted from leukocytes was able to bind the amount of iron corresponding to its theoretical iron-binding capacity. After injection of endotoxin into rats, lactoferrin was detected in various tissues where it was normally absent, or in the plasma when the reticuloendothelial system (RES) had previously been blocked by injections of India ink or aggregated albumin. (b) Lactoferrin is Able to Remove the Iron from Transferrin. Significant exchange of iron from transferrin to lactoferrin was observed in vitro only at a pH below 7.0 or in the presence of a high concentration of citrate. However, the fast elimination of lactoferrin in vivo, when saturated with iron, might account for the observed transfer of iron to endogenous or administered apolactoferrin. Intravenous injection of human apolactoferrin into rats caused a marked decrease of the plasma iron level. The kinetics of this process, as well as controls with other proteins, ruled out the possibility of a secondary inflammatory effect due to phlogogenic contaminants. (c) Fe-Lactoferrin is Taken-up by the RES. By immunofluorescence, lactoferrin was shown to be bound and ingested by monocytes. The rate of elimination of human Fe-lactoferrin injected into rats was particularly fast when compared to that of human apolactoferrin, succinylated Fe-lactoferrin, or other human proteins. Blockade of the RES slowed down the rate of clearance of Fe-lactoferrin and was also found to retard the elimination of endogenous rat lactoferrin released by endotoxin. These experiments suggest the existence of specific receptors for Fe-lactoferrin on the membrane of macrophages.

Topics: Animals; Apoproteins; Humans; Hydrogen-Ion Concentration; Immunodiffusion; Immunoelectrophoresis; Inflammation; Iron; Iron Radioisotopes; Lactoferrin; Lactoglobulins; Mononuclear Phagocyte System; Neutrophils; Phagocytosis; Rabbits; Rats; Transferrin