lactoferrin and Hypoxia

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

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

Obesity is a global epidemic, it can induce glucose and lipid metabolism disorder and non-alcoholic fatty liver disease (NAFLD). This study explored a new way to control weight and improve fatty liver, namely, living in hypoxia environment and supplement with lactoferrin (Lf). Sixty male C57BL/6J mice were divided into six groups, namely, control, hypoxia, high-fat diet, hypoxia + high-fat diet, hypoxia + high-fat diet + low dose Lf intervention, and hypoxia + high-fat diet + high-dose Lf intervention. Mice in the hypoxia treatment groups were treated with approximately 11.5 % oxygen for 6 h every day for 8 weeks. Results showed that interventions combining Lf and hypoxia treatments showed better effect against obesity and NAFLD than hypoxia treatment alone. The interventions controlled weight gain in mice, improved glucolipid metabolism in mice. The combination intervention reduced cholesterol absorption by reducing the level of hydrophobic bile acids, and elevating the level of hydrophilic bile acids. Gut microbiota analysis revealed that the combination intervention considerably elevated short chain fatty acids (SCFAs)-producing bacteria level, and reduced the Desulfovibrionaceae_unclassified level. Thus, Lf combined with hypoxia intervention effectively prevents obesity and NAFLD by restoring gut microbiota composition and bile acid profile.

Topics: Animals; Bile Acids and Salts; Diet, High-Fat; Hypoxia; Lactoferrin; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

The protective effects of recombinant human lactoferrin rhLF (branded "CAPRABEL™") on the cognitive functions of rat offspring subjected to prenatal hypoxia (7% O

Topics: Animals; Cognition; Erythropoietin; Female; Hypoxia; Lactoferrin; Pregnancy; Rats; Recombinant Proteins; Vitamins

The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown.. Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release.. Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.

Topics: Apoptosis; Blotting, Western; Cell Degranulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypoxia; Immunohistochemistry; Lactoferrin; Leukocyte Elastase; Matrix Metalloproteinase 9; Microscopy, Electron; Neutrophil Activation; Neutrophils; Peroxidase; Platelet Activating Factor; Real-Time Polymerase Chain Reaction; Receptors, Formyl Peptide; Signal Transduction; Up-Regulation

Apo-form of human lactoferrin (LF) is a potent iron chelator, this feature being similar to the iron-binding properties of a synthetic chelator desferoxamine (DFO). The latter stabilizes the principal adaptive transcriptional hypoxia-inducible factor-1 alpha (HIF-1α). Since DFO is known as a pharmacological mimetic of hypoxia it was decided to test whether apo-LF is able to perform as such. Mice either injected intraperitoneally or given per os apo-LF displayed HIF-1α in liver, lungs, heart, brain, spleen and kidneys, as judged by results of Western blotting. Similar administration of iron-saturated LF (75 mg/kg) did not bring forth such effect. Synthesis of erythropoietin and ceruloplasmin became increased in the first case, which is explained by the respective genes being targets for HIF-1α. Apo-LF, but not Fe-LF, injected intraperitoneally to hypoxia low-resistant mice 24 h before animals were subjected to normobaric hypoxia with hypercapnia caused a significant increase of life-time by 40 %. The results obtained show that, like DFO, apo-LF performs as a normoxic mimetic of hypoxia, capable of stabilizing HIF-1α. Protective features of LF and DFO and their pharmacological properties involving HIF-1α are discussed.

Topics: Apoproteins; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lactoferrin

In this study, we hypothesized that the lung actively releases excess iron into the circulation to regulate iron homeostasis. We measured nonheme iron (NHFe) in the perfusate of control isolated perfused rabbit lungs and lungs with ischemia-reperfusion (I/R) ventilated with normoxic (21% O(2)) or hypoxic (95% N(2)) gas mixtures. Some were perfused with bicarbonate-free (HEPES) buffer or treated with the anion exchange inhibitor DIDS. The control lungs released approximately 0.25 microg/ml of NHFe or 20% of the total lung NHFe into the vascular space that was not complexed with ferritin, transferrin, or lactoferrin or bleomycin reactive. The I/R lungs released a similar amount of NHFe during ischemia and some bleomycin-detectable iron during reperfusion. NHFe release was attenuated by approximately 50% in both control and ischemic lungs by hypoxia and by >90% in control lungs and approximately 60% in ischemic lungs by DIDS and HEPES. Reperfusion injury was not affected by DIDS or HEPES but was attenuated by hypoxia. These results indicate that biologically nonreactive nonheme iron is released rapidly by the lung into the vascular space via mechanisms that are linked to bicarbonate exchange. During prolonged ischemia, redox-active iron is also released into the vascular compartment by other mechanisms and may contribute to lung injury.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Animals; Anion Exchange Protein 1, Erythrocyte; Bicarbonates; Bleomycin; Ferritins; Hypoxia; In Vitro Techniques; Iron; Ischemia; Lactoferrin; Lung; Male; Perfusion; Pulmonary Circulation; Rabbits; Reperfusion Injury; Transferrin