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Protective effect of Linomide on TNF-alpha-induced hepatic injury
Daniel Klintman1, Gunnar Hedlund, Henrik Thorlacius
1Department of Surgery, Malm University Hospital, Lund University, S-205 02 Malmö, Sweden.
Background/Aims:
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).
Methods:
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.
Results:
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.
Conclusions:
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.