lactoferrin and Systemic-Inflammatory-Response-Syndrome

Lactoferrin, an iron-binding glycoprotein, is a cell-secreted mediator that bridges innate and adaptive immune function in mammals. It is a pleiotropic molecule that directly assists in the influence of presenting cells for the development of T-helper cell polarization. The aim of this review is to provide an overview of research regarding the role of lactoferrin in maintaining immune homeostasis, in particular as a mediator of immune responses to infectious assault, trauma and injury. These findings are critically relevant in the development of both prophylactic and therapeutic interventions in humans. Understanding these particular effects of lactoferrin will provide a logical framework for determining its role in health and disease.

Topics: Animals; Humans; Immunity, Cellular; Immunity, Innate; Immunologic Factors; Lactoferrin; Oxidative Stress; Receptors, Cell Surface; Staphylococcal Infections; Systemic Inflammatory Response Syndrome

The gastrointestinal tract is the largest surface area of the body and the primary site for microorganisms, foreign antigens and toxins to gain entry to the host's internal milieu. The use of enteral feedings enriched with immune-enhancing ingredients is attracting considerable interest because there is increasing application of enteral feeding and appreciation of the role of the gut in the development of infection and of multiple organ failure in critically ill patients.. in this review, we will discuss nutrients, such as glutamine, arginine, omega 3 fatty acids, nucleotides, probiotics, and lactoferrin, and how they might be used as immunonutrients in neonatal clinics.

Topics: Adjuvants, Immunologic; Digestive System; Enteral Nutrition; Glutamine; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Intensive Care Units, Neonatal; Lactoferrin; Probiotics; Systemic Inflammatory Response Syndrome

This review addresses our present-day knowledge on the role of different cellular adhesion molecules, cytokines and glycoproteins for the detection of sepsis-induced injury in the microvasculature of the human lung using immunohistochemistry. Through the induction and modulation of endothelial cell adhesion molecules, such as E-selectin (CD 62E), the vascular endothelium controls leukocyte extravasation into tissue. E-Selectin, not expressed by unstimulated endothelium, is activated by cytokines and initiates neutrophil recruitment in sepsis-induced lung injury. Since E-selectin is strongly expressed in the pulmonary microvasculature in sepsis-associated fatalities, the immunohistochemical detection of an intense expression of E-selectin in lung tissue is a valuable diagnostic tool in the forensic postmortem elucidation of death due to sepsis. VLA-4 (CD49d/CD29) is strongly expressed on intravascular, interstitial and intra-alveolar leukocytes in sepsis-associated fatalities, whereas in non-septic fatalities an irregular weak immunoreactivity can be observed on interstitial leukocytes and no positive immunohistochemical expression can be observed on intravascular or intra-alveolar leukocytes. ICAM-1 (CD54) is strongly expressed on endothelial cells of the pulmonary microvasculature and on pulmonary macrophages and lymphocytes in sepsis-associated fatalities. In contrast, an infrequent weak immunohistochemical reaction for ICAM-1 is found on pulmonary endothelium and on perivascular leukocytes in non-septic fatalities. The up-regulation of both cellular adhesion molecules can be considered as an useful immunohistochemical postmortem marker of sepsis. Lactoferrin (LF) is an iron-binding glycoprotein located in specific (secondary) granules of leukocytes and plays a central role in the host response to infectious stimuli in providing both bacteriostatic and bactericidal protection. There is a statistically significant association between an enhanced expression of LF on pulmonary leukocytes in sepsis-related fatalities in contrast to non-septic controls. The immunohistochemical detection of an enhanced expression of LF can contribute to the postmortem discrimination between sepsis and non-septic fatalities. Application of carbohydrate-specific lectins (ConA, UEA, GSA I, GSA II, MPA, PNA, Jac, WGA, MAA, LPA, SNA) on deparaffinated lung tissue sections from sepsis-associated fatalities and control cases results to some extent in different staining patterns of a

Topics: Autopsy; Biomarkers; E-Selectin; Humans; Immunohistochemistry; Integrin alpha4beta1; Intercellular Adhesion Molecule-1; Lactoferrin; Lectins; Lung; Microcirculation; Systemic Inflammatory Response Syndrome; Vascular Endothelial Growth Factor A

Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.

Topics: Acetaldehyde Dehydrogenase Inhibitors; Animals; Anti-Inflammatory Agents; Biomimetic Materials; Colitis, Ulcerative; COVID-19; COVID-19 Drug Treatment; Disease Models, Animal; Disulfiram; Drug Carriers; Humans; Immunosuppressive Agents; Lactoferrin; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; Pyroptosis; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Treatment Outcome

Dynamic measurements of blood TNF-a, IL-IRA, CRP, oligopeptide, and lactoferrin levels in patients with systemic and local soft tissue infections revealed direct correlation between them which allowed to use these indicators for the diagnosis of systemic infections. Results of clinical and laboratory analyses provided a basis for distinguishing short-term systemic inflammatory response syndrome and sepsis and developing relevant diagnostic criteria. Sepsis combined with systemic inflammatory response syndrome persisting for more than 72 hours after the onset of adequate therapy was characterized by CRP levels > 30 mg/l, oligopeptides > 0.34 U, lactoferrin > 1900 ng/ml, TNF-a > 6 pg/ml, ILL-IRA < 1500 pg/ml Patients with systemic inflammatory response syndrome for less than 72 hours had lower TNF-a, CRP, oligopeptide, and lactoferrin levels with IL-IRA > 1500 pg/ml. This new approach to early diagnosis of systemic infections makes it possible to optimize their treatment and thereby enhance its efficiency.

Topics: Biomarkers; C-Reactive Protein; Clinical Laboratory Techniques; Humans; Interleukin 1 Receptor Antagonist Protein; Lactoferrin; Oligopeptides; Soft Tissue Infections; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Mice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo. Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h post-shock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-alpha (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-alpha and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.

Topics: Animals; Drug Administration Schedule; Drug Evaluation, Preclinical; Endotoxemia; Feedback; Humans; Inflammation Mediators; Injections, Intraperitoneal; Interleukin-10; Interleukin-6; Lactoferrin; Lipopolysaccharides; Mice; Models, Animal; Nitric Oxide; Respiratory Burst; Shock, Septic; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

The aim of the study was to investigate whether lactoferrin can improve the immune competence of cells from patients with systemic inflammatory response syndrome (SIRS). We studied the effect of lactoferrin (LF) on the proliferative response of peripheral blood mononuclear cells (PBMC) to lipopolisaccharide (LPS) in vitro and its influence on production of 2 proinflammatory cytokines: interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). Three groups of patients: septic survivors, septic nonsurvivors and multiple trauma patients, were investigated. Blood samples were taken upon admission to intensive care unit and after 2, 3 and 5 days. The proliferative response of PBMC in vitro was tested using 3-day culture with LPS. Cell proliferation/death was measured using MTT colorimetric method. The spontaneous and LPS-induced activity of TNF-alpha and IL-6 were measured with bioassays using indicator cell lines WEHI-164.13 and 7TD1, respectively. We demonstrated that LF inhibited the proliferative response, both spontaneous and LPS-induced, in all groups of patients. Lactoferrin alone was a good inducer of IL-6 and TNF-alpha production by monoclear cells in vitro. Addition of LF to the cultures of LPS-activated mononuclear cells stimulated IL-6 production, most markedly in the group of septic survivor patients (mean 1479, 1452, 1728, 1980 pg/ml on day 1, 2, 3 and 6 respectively). Lactoferrin also upregulated TNF-alpha production. That effect was very significant in the septic survivor patients (mean 7407, 6739, 7498 and 8509 pg/ml on day 1, 2, 3 and 5 respectively) and less pronounced in the group of trauma patients. We conclude that lactoferrin exhibited regulatory actions on the altered reactivity of PBMC from patients with sepsis and multiple injury. Lactoferrin is a good inducer of IL-6 and TNF-alpha production. However, in most cases of septic nonsurvivors LF could not abolish low reactivity of cells with regard to cytokine production.

Topics: Adolescent; Adult; Aged; Cells, Cultured; Critical Illness; Female; Humans; Interleukin-6; Lactoferrin; Leukocytes, Mononuclear; Lipopolysaccharides; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha