Protective effect of Linomide on TNF-alpha-induced hepatic injury.
OBJECTIVE
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.
Klintman
Daniel
D
Department of Surgery, Malm University Hospital, Lund University, S-205 02 Malmö, Sweden.
Hedlund
Gunnar
G
Thorlacius
Henrik
H
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury; D004730:Endothelium, Vascular / Q000166:cytology; D005688:Galactosamine; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology*; D007962:Leukocytes / Q000166:cytology; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D014409:Tumor Necrosis Factor-alpha; C045282:roquinimex; D005688:Galactosamine