chiniofon and Chemical-and-Drug-Induced-Liver-Injury

The immunomodulator Linomide has been shown to protect against septic liver injury by reducing hepatic accumulation of leukocytes although the detailed anti-inflammatory mechanisms remain elusive. This study examined the effect of Linomide on the production of CXC chemokines, including macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) and interleukin-10 (IL-10) in lipopolysaccharide (LPS)/d-galactosamine (Gal)-induced liver injury in mice. It was found that pretreatment with 300 mg kg(-1) of Linomide markedly suppressed leukocyte recruitment, perfusion failure, and hepatocellular damage and apoptosis in the liver of endotoxemic mice. Administration of Linomide inhibited endotoxin-induced gene expression of MIP-2 and KC and significantly reduced the hepatic production of MIP-2 and KC by 63 and 80%, respectively. Moreover, it was found that Linomide increased the liver content of IL-10 by more than three-fold in endotoxemic mice. The protective effect of Linomide against endotoxin-induced inflammation and liver injury was abolished in IL-10-deficient mice, suggesting that the beneficial effect of Linomide is dependent on the function of IL-10. Taken together, these novel findings suggest that the protective effect of Linomide is mediated via local upregulation of IL-10, which in turn decreases the generation of CXC chemokines and pathological recruitment of leukocytes in the liver of endotoxemic mice.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Chemokine CXCL1; Chemokines, CXC; Endotoxins; Enzyme-Linked Immunosorbent Assay; Hydroxyquinolines; Immunologic Factors; Intercellular Signaling Peptides and Proteins; Interleukin-10; Interleukin-16; Leukocytes; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction

Linomide is an immunomodulator that ameliorates several autoimmune and inflammatory diseases. We assessed the effect of Linomide on microvascular perfusion failure, leukocyte recruitment and hepatocellular injury induced by tumor necrosis factor alpha (TNF-alpha) and D-Galactosamine (Gal).. After 3 days of Linomide pretreatment (1, 10 and 100 mg/kg/day), rats were challenged with TNF-alpha/Gal for 24 h. Microvascular perfusion, leukocyte-endothelium interactions in hepatic postsinusoidal venules and leukocyte sequestration in sinusoids were evaluated using intravital microscopy. Liver enzymes were measured spectrophotometrically.. Challenge with TNF-alpha/Gal significantly reduced sinusoidal perfusion, and increased leukocyte rolling, adhesion and liver enzymes. Interestingly, pretreatment with Linomide (10 and 100 mg/kg/day) significantly reduced TNF-alpha/Gal-induced leukocyte rolling by 65 and 63%, and leukocyte adhesion by 87 and 84%, respectively. Moreover, Linomide (10 and 100 mg/kg/day) decreased sinusoidal sequestration of leukocytes by 71 and 51%, and markedly improved sinusoidal perfusion. Moreover, Linomide reduced aspartate aminotransferase by 87-97%, and alanine aminotransferase by 79-96%. However, Linomide had no protective effect when administered concomitantly with TNF-alpha/Gal.. These data demonstrate a dose-dependent inhibitory effect of Linomide on perfusion failure, leukocyte recruitment and hepatocellular injury provoked by TNF-alpha. Indeed, these findings suggest that Linomide may be an effective substance for protection of the liver in sepsis.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Cell Adhesion; Cell Communication; Chemical and Drug Induced Liver Injury; Endothelium, Vascular; Galactosamine; Hydroxyquinolines; Leukocytes; Liver; Liver Diseases; Male; Microcirculation; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Anti-Infective Agents; Chemical and Drug Induced Liver Injury; Drug Combinations; Female; Humans; Hydroxyquinolines; Middle Aged; Oxyquinoline