Advanced

Protective effect of Linomide on TNF-alpha-induced hepatic injury.

Klintman, Daniel LU ; Hedlund, Gunnar and Thorlacius, Henrik LU (2002) In Journal of Hepatology 36(2). p.226-232
Abstract
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 100mg/kg/day), rats were challenged with TNF-alpha/Gal for 24h. 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... (More)
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 100mg/kg/day), rats were challenged with TNF-alpha/Gal for 24h. 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 100mg/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 100mg/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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell Communication/drug effects/immunology, Endothelium, Cell Adhesion/drug effects/immunology, Vascular/cytology, Galactosamine, Hydroxyquinolines/chemistry/*pharmacology, Leukocytes/cytology, Liver/pathology, Liver Diseases/chemically induced/*drug therapy/*pathology, Male, Microcirculation/drug effects, Rats, Sprague-Dawley, Support, Non-U.S. Gov't, Tumor Necrosis Factor, Antineoplastic Agents, Animal, Immunologic/chemistry/*pharmacology, Adjuvants, Sepsis/drug therapy
in
Journal of Hepatology
volume
36
issue
2
pages
226 - 232
publisher
Elsevier
external identifiers
  • pmid:11830334
  • wos:000174038900011
  • scopus:0036169985
ISSN
0168-8278
DOI
10.1016/S0168-8278(01)00261-6
language
English
LU publication?
yes
id
86cd5cda-0c69-4e10-b9a5-1698e3c4d657 (old id 106151)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11830334&dopt=Abstract
date added to LUP
2007-07-24 15:57:14
date last changed
2017-01-01 04:25:46
@article{86cd5cda-0c69-4e10-b9a5-1698e3c4d657,
  abstract     = {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 100mg/kg/day), rats were challenged with TNF-alpha/Gal for 24h. 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 100mg/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 100mg/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.},
  author       = {Klintman, Daniel and Hedlund, Gunnar and Thorlacius, Henrik},
  issn         = {0168-8278},
  keyword      = {Cell Communication/drug effects/immunology,Endothelium,Cell Adhesion/drug effects/immunology,Vascular/cytology,Galactosamine,Hydroxyquinolines/chemistry/*pharmacology,Leukocytes/cytology,Liver/pathology,Liver Diseases/chemically induced/*drug therapy/*pathology,Male,Microcirculation/drug effects,Rats,Sprague-Dawley,Support,Non-U.S. Gov't,Tumor Necrosis Factor,Antineoplastic Agents,Animal,Immunologic/chemistry/*pharmacology,Adjuvants,Sepsis/drug therapy},
  language     = {eng},
  number       = {2},
  pages        = {226--232},
  publisher    = {Elsevier},
  series       = {Journal of Hepatology},
  title        = {Protective effect of Linomide on TNF-alpha-induced hepatic injury.},
  url          = {http://dx.doi.org/10.1016/S0168-8278(01)00261-6},
  volume       = {36},
  year         = {2002},
}