lactoferrin and Hepatitis

Accumulating evidence suggests that orally ingested lactoferrin protects against inflammation. To assess the efficacy of orally administered bovine lactoferrin (bLF) against hepatitis and to identify the underlying mechanism, in the present study, we used four mouse models of hepatitis induced by d-galactosamine (GalN), carbon tetrachloride (CCl4), GalN plus lipopolysaccharide (LPS) and zymosan plus LPS. Intraperitoneal (i.p.) injection of GalN (500 mg/kg body weight) in mice treated with bovine serum albumin (BSA) for 14 d significantly increased serum aspartate aminotransferase (AST) concentrations compared with the untreated mice. However, orally administered bLF reduced AST concentrations compared with BSA treatment. In mice that received a single injection (0·4 ml/kg) and twice-weekly injections (0·08 ml/kg) of CCl4 for 24 weeks and pretreated with bLF for 14 d and 24 weeks, respectively, significantly suppressed alanine aminotransferase and AST concentrations were observed compared with the BSA-treated control. Oral administration of bLF for 14 d before i.p. injection of LPS (5 mg/kg) plus GalN (1 g/kg) significantly improved the survival rate. In mice that received intravenous injection of zymosan (25 mg/kg) and LPS (15 μg/kg) at 7 d intervals, bLF reduced the elevation of AST concentrations and enhanced the production of IL-11 and bone morphogenetic protein 2 in the small intestine compared with the BSA-treated control. To evaluate the effects of IL-11, we used IL-11 receptor α-null mice treated with GalN, CCl4 and zymosan plus LPS. In this group, the activity of bLF was not significantly different from that of BSA. These data indicate that orally ingested bLF enhances the expression of IL-11 in the small intestine and up-regulates protective activity in mice with hepatitis.

Topics: Administration, Intravenous; Administration, Oral; Alanine Transaminase; Analysis of Variance; Animals; Bone Morphogenetic Protein 2; Cattle; Disease Models, Animal; Hepatitis; Interleukin-11; Intestine, Small; Lactoferrin; Liver; Mice; Mice, Inbred Strains; RNA, Messenger; Serum Albumin, Bovine; Tumor Necrosis Factor-alpha; Up-Regulation

Orally administered bovine lactoferrin (bLF) exerts an anti-inflammatory effect on hepatitis and colitis animal models. To investigate the mechanism underlying the action of bLF, we explored the expression of inflammation-related factors in the intestine of a hepatitis mouse model after the oral administration of bLF and in several human intestinal cell lines treated with bLF.. The effects of bLF on the expression of interleukin-11 (IL-11) and bone morphogenetic protein 2 (BMP2) in the intestinal mucosa of a hepatitis mouse model as well as in cell cultures of human intestinal epithelial cells, myofibroblasts, and monocytes were examined using the real-time reverse transcription polymerase chain reaction. Epithelial cells and myofibroblasts were also cocultured using transwells. bLF transport, and IL-11 and BMP2 induction, as well as the interactions between the two cell types, were then analyzed after bLF treatment.. In vivo, oral bLF administration increased the production of IL-11 and BMP2 in intestinal specimens. In vitro, bLF only stimulated the production of IL-11 in human intestinal myofibroblasts; i.e., it had no effect on BMP2 production in any cell type. In the transwell cocultures, bLF passed through the epithelium and directly stimulated IL-11 production in the myofibroblasts on the basolateral side. The IL-11 produced in the myofibroblasts subsequently acted protectively on the epithelial cells of the coculture.. bLF upregulated the activity of anti-inflammatory factors, such as IL-11, in the intestine of a hepatitis mouse model and human intestinal myofibroblasts.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Bone Morphogenetic Protein 2; Caco-2 Cells; Cattle; Disease Models, Animal; Hepatitis; Humans; Interleukin-11; Intestinal Mucosa; Lactoferrin; Mice; Mice, Inbred BALB C; Myofibroblasts

Liver diseases, caused by viral infection, autoimmune conditions, alcohol ingestion or the use of certain drugs, are a significant health issue, as many can develop into liver failure. Lactoferrin (Lac) is an iron-binding glycoprotein that belongs to the transferrin family. Owing to its multiple biological functions, Lac has been evaluated in a number of clinical trials to treat infections, inflammation and cancer.. The present study aims to reveal a profound hepatoprotective effect of Lac, using a mouse model of Concanavalin A (Con A)-induced hepatitis, which mimics the pathophysiology of human viral and autoimmune hepatitis.. C57Bl/6J mice were injected with bovine Lac following Con A challenge. The effects of Lac on interferon (IFN)-gamma and interleukin (IL)-4 expression were determined. The roles of Lac on T-cell apoptosis and activation, and leukocytes infiltration were examined.. The data demonstrated that the protective effect of Lac was attributed to its ability to inhibit T-cell activation and production of IFN-gamma, as well as to suppress IL-4 production by hepatic natural killer T cells.. These findings indicate a great therapeutic potential of Lac in treating in treating inflammatory hepatitis and possibly other inflammatory diseases.

Topics: Animals; Cattle; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytokines; Disease Models, Animal; Flow Cytometry; Hepatitis; Immunohistochemistry; Interferons; Interleukin-4; Lactoferrin; Liver; Male; Mice; Mice, Inbred C57BL; Probability; Random Allocation; Th1 Cells

To assess the effect of lactoferrin on oxidative liver damage and its mechanism, we used Long-Evans Cinnamon (LEC) rats that spontaneously develop fulminant-like hepatitis and lethal hepatic failure.. Four-week-old female LEC rats were divided into the untreated and treated groups. The latter was fed bovine lactoferrin at 2% mixed with conventional diet.. The cumulative survival rates were 75.0% vs. 100% at 14 weeks, 37.5% vs. 91.7% at 15 weeks, and 12.5% vs. 91.7% at 16 weeks, respectively, for untreated and treated rats (P=0.0008). The 8-OHdG levels in liver mitochondrial DNA and malondialdehyde in plasma and liver tissues were significantly lower in treated than untreated rats (P<0.001, =0.017 and 0.034, respectively). Mitochondrial DNA mutations were more common in untreated rats. OGG1 mRNA and protein expression levels were significantly lower in untreated than treated rats (P=0.003 and 0.007, respectively). Hypermethylation of the second CpG island located upstream of OGG1 gene was observed in untreated rats.. Our findings indicated that lactoferrin inhibits oxidative liver damage in LEC rats. Lactoferrin could be potentially useful for the treatment of oxidative stress-induced liver diseases.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Caspase 3; Cattle; CpG Islands; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA Glycosylases; DNA Methylation; DNA Repair; DNA, Mitochondrial; Down-Regulation; Female; Hepatitis; Lactoferrin; Liver; Liver Failure, Acute; Malondialdehyde; Mitochondria, Liver; Rats; Rats, Inbred LEC

Lactoferrin (Lf) expression has been immunohistochemically investigated in 117 formalin-fixed paraffin-embedded liver bioptic samples obtained from an equal number of patients affected by chronic hepatitis (HCV = 76; HBV = 17; HBV + HDV = 14; cryptogenetic = 10); in addition, 10 autoptic specimens of normal liver were studied as control. The Lf immunoreactivity was evaluated by an intensity-distribution (ID) score. The Lf immunoexpression was observed in 88 out of 117 (75%) cases of chronic hepatitis; interestingly, all liver specimens from HBV hepatitis showed a constant Lf reactivity with the highest ID-score, whereas the evidence of Lf was encountered in 54/76 (71.1%) HCV as well as in 11/14 (78.6%) HDV chronic hepatitis, thus documenting a variable degree of Lf immunostaining in relation to different viruses. Moreover, in 6/10 (60%) cases of cryptogenetic hepatitis Lf immunoexpression was documented, whereas all normal liver controls were unreactive. In HCV specimens, the Lf nuclear immunoreactivity appeared to increase with the progression of the disease, with a greater expression in genotype 1. In contrast, no relationship among Lf ID-scores and different stages or grades of HBV, HDV or cryptogenetic hepatitis was encountered. This fact may suggest a role for Lf as an unspecific defensive agent in chronic inflammatory liver diseases, similarly to that elsewhere reported in other inflammatory tissue injuries.

Topics: Adult; Aged; Cell Nucleus; Coloring Agents; Cytoplasm; Female; Hepatitis; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis C; Hepatitis, Chronic; Hepatitis, Viral, Human; Hepatocytes; Humans; Immunohistochemistry; Lactoferrin; Liver; Male; Middle Aged

BALB/c mice were intravenously injected with lipopolysaccharide (LPS) (0.05 microg/g of body weight) 7 days after being primed with zymosan. Recombinant human lactoferrin (250 microg/g of body weight), intravenously administered 1 day before the injection of LPS, significantly lessened the severity of hepatitis, as assessed by levels of serum alanine transaminase compared to those seen when casein was administered. The transient rise of serum tumor necrosis factor alpha (TNF-alpha) after LPS treatment was also significantly lowered by the intravenous administration of lactoferrin, suggesting that the effect of lactoferrin was due to the suppression of TNF-alpha production. The following results indicate that the sites of action of lactoferrin for the suppression of the development of this type of hepatitis are Kupffer cells. Gadolinium chloride, a substance known to eliminate Kupffer cells, administered 1 day before LPS, inhibited the transient rise of TNF-alpha and protected against the development of hepatitis. Kupffer cells isolated from mice intraperitoneally injected with recombinant human lactoferrin became refractory to LPS. The specific interaction of recombinant human lactoferrin with the Kupffer cells was shown by a binding assay, which revealed two types of binding sites on mouse Kupffer cells. Of the two dissociation constants determined in this way, the lower dissociation constant, 0.47 x 10(-6) M, was within the range of the 50% effective doses for the suppression of TNF-alpha production. These results suggest that recombinant human lactoferrin administered to mice suppresses the production of TNF-alpha by Kupffer cells by directly associating with the binding sites on these cells.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Gadolinium; Hepatitis; Humans; Injections, Intravenous; Kupffer Cells; Lactoferrin; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Recombinant Proteins; Tumor Necrosis Factor-alpha; Zymosan

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