lactoferrin and Fibrosis

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

Renal fibrosis is a hallmark feature of chronic kidney diseases (CKDs). However, despite the increased prevalence of renal fibrosis, there is no approved antifibrotic drug for the management of renal fibrosis. Cerium oxide nanoparticles (CONPs) have been demonstrated to possess a number of properties including antioxidant, anti-inflammatory and nephroprotective activity. As the kidneys are rich in lactoferrin (Lf) receptors, we synthesised the lactoferrin-CONP (Lf-CONP) system to be used for active targeting of the kidneys and provide antifibrotic effects of CONPs to the kidneys. We used the unilateral ureteral obstruction (UUO)-induced renal fibrosis model and treated the animals with Lf-CONP to observe the antifibrotic effects of Lf-CONP. Lf-CONP was found to inhibit the progression of renal fibrosis in a superior manner when compared to CONPs alone.

Topics: Animals; Fibrosis; Kidney; Kidney Diseases; Lactoferrin; Renal Insufficiency, Chronic; Transforming Growth Factor beta1

Several epidemiological studies regarding the adverse effect of air pollution have notably accelerated in recent years. Urban particulate matter (PM) gains access to the respiratory system and translocates into the circulation to affect several tissues, such as the liver and kidneys. Lactoferrin is a substance belonging to the non-heme iron-binding glycoprotein which is present in breast milk and other exocrine fluids. Lactoferrin is protective against many pathophysiological conditions. In the present study, we explored the potential influence of lactoferrin on PM-induced nephrotoxicity. We found that lactoferrin rescued PM-induced cell death but did not affect apoptosis in human kidney cells. Lactoferrin decreased necroptosis and fibrosis but increased autophagy in human kidney cells. Furthermore, the gene expression profiles of PM and lactoferrin were analyzed by RNA sequencing. The transcriptional profiles were uploaded and analyzed by ingenuity pathway analysis software and gene set enrichment analysis. The results showed that the crucial role of the CSF2/CENPE pathway was involved in human kidney cells treated with PM and lactoferrin. In a mouse model, lactoferrin ameliorates PM-induced nephrotoxicity by regulating necroptosis, fibrosis, autophagy and the CSF2/CENPE axis. In summary, these findings showed that lactoferrin could be a novel therapeutic or preventive agent for renal disorders caused by airborne PM pollution.

Topics: Animals; Apoptosis; Fibrosis; Humans; Kidney; Lactoferrin; Mice; Particulate Matter

Non-alcoholic steatohepatitis (NASH) can cause liver cirrhosis and hepatocellular carcinoma (HCC), with cases increasing worldwide. To reduce the incidence of liver cirrhosis and HCC, NASH is targeted for the development of treatments, along with viral hepatitis and alcoholic hepatitis. Lactoferrin (LF) has antioxidant, anti-cancer, and anti-inflammatory activities. However, whether LF affects NASH and fibrosis remains unelucidated. We aimed to clarify the chemopreventive effect of LF on NASH progression. We used a NASH model with metabolic syndrome established using connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rats. Cx32ΔTg rats (7 weeks old) were fed a high-fat diet and intraperitoneally injected with dimethylnitrosamine (DMN). Rats were divided into three groups for LF treatment at 0, 100, or 500 mg/kg/day for 17 weeks. Lactoferrin significantly protected steatosis and lobular inflammation in Cx32ΔTg rat livers and attenuated bridging fibrosis or liver cirrhosis induced by DMN. By quantitative RT-PCR, LF significantly down-regulated inflammatory (

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Carcinoma, Hepatocellular; Connexins; Cytokines; Dimethylnitrosamine; Fibrosis; Gap Junction beta-1 Protein; Lactoferrin; Liver; Liver Cirrhosis; Liver Neoplasms; Male; NF-kappa B; Non-alcoholic Fatty Liver Disease; Rats; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha