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Cytokine‐induced upregulation of hepatic intercellular adhesion molecule‐1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure
Author(s) -
Essani Naeem A.,
Fisher Michael A.,
Farhood Anwar,
Manning Anthony M.,
Wayne Smith C.,
Jaeschke Hartmut
Publication year - 1995
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840210623
Subject(s) - tumor necrosis factor alpha , downregulation and upregulation , liver injury , cd18 , icam 1 , cell adhesion molecule , intercellular adhesion molecule 1 , cytokine , proinflammatory cytokine , integrin alpha m , immunology , biology , inflammation , endocrinology , biochemistry , immune system , gene
Neutrophil‐induced liver injury during endotoxemia is dependent on the adhesion molecule Mac‐1 (CD11b/CD18) on neutrophils. The potential involvement of its counterreceptor, intercellular adhesion molecule—1 (ICAM‐1), in the pathogenesis was investigated after administration of 100 μg/kg Salmonella abortus equi endotoxin (ET) in galactosamine‐sensitized mice (Gal). In ET‐sensitive mice (C3Heb/FeJ), which generated large amounts of tumor necrosis factor—alpha (TNF‐α), massive neutrophil infiltration and severe liver injury were observed. In an ET‐resistant strain (C3H/HeJ), which did not generate TNF‐α, Gal/ET failed to cause neutrophil accumulation or injury. ICAM‐1 messenger RNA (mRNA), negligible in control livers, was selectively induced by Gal/ET in ET‐sensitive mice. Intravenous injection of murine TNF‐α, interleukin‐1 alpha (IL‐1α) or IL‐1β (13 to 23 μg/kg) strongly induced the ICAM‐1 message in both strains, showing a comparable capacity for ICAM‐1 mRNA synthesis. All cytokines caused similar neutrophil accumulation in the liver; however, only Gal/TNF‐α also caused upregulation of Mac‐1 on circulating neutrophils and liver injury. The anti‐murine ICAM‐1 monoclonal antibody YN.1 (3 mg/kg) attenuated liver injury in ET‐sensitive mice by 67% to 90% compared with isotype‐matched control antibody‐treated animals but did not reduce neutrophil accumulation in hepatic sinusoids. Our data suggest that the cytokines TNF‐α and IL‐1 are the main mediators responsible for upregulation of ICAM‐1 mRNA in the liver during endotoxemia. The upregulation of both adhesion molecules, ICAM‐1 and Mac‐1, is necessary for a neutrophil‐induced liver injury to occur. Blocking ICAM‐1 and/or interfering with ICAM‐1 induction could be a successful therapeutic strategy to prevent sepsis‐related inflammatory liver injury.