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Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism
H Jaeschke1, A Farhood, C W Smith
1Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Abstract:
To investigate the role of neutrophils (PMNs) and PMN-dependent adhesion molecules in the pathogenesis of liver injury in a model of endotoxin shock, male ICR mice received a dose of 700 mg/kg galactosamine and 100 micrograms/kg Salmonella abortus equi endotoxin. PMNs accumulated continuously in the liver, reaching values of 446 +/- 71 PMNs/50 high-power fields at 9 h (basal value 18 +/- 7). Plasma alanine aminotransferase activities as index of parenchymal cell injury did not change up to 5 h posttreatment (basal value 35 +/- 5 U/l) but increased to 1,950 +/- 460 U/l at 9 h. The formation of glutathione disulfide (GSSG) in plasma as an index of an extracellular oxidant stress also increased only at 9 h. Pretreatment of animals with monoclonal antibodies against the CD11b and CD18 subunits of the CD11/CD18 integrin family on the surface of the PMN reduced the number of PMNs in the liver by 50% and significantly attenuated liver injury and GSSG formation. An anti-CD11a and a nonbinding control antibody were ineffective. It is concluded that PMNs are actively involved in the pathogenesis of galactosamine and endotoxin shock and that at least in part the accumulation of PMNs, the subsequent oxidant stress, and the tissue injury in this model of experimental hepatitis are CD11b/CD18 (Mac-1) dependent.
Insights
Neutrophils (PMNs) drive liver injury in endotoxin shock. Blocking CD11b/CD18 adhesion molecules on PMNs reduced liver damage and oxidant stress, indicating their critical role in this experimental hepatitis model.
Area of Science:
- Immunology
- Hepatology
- Pathophysiology
Background:
- Liver injury is a critical component of endotoxin shock.
- Neutrophils (PMNs) are implicated in inflammatory processes and tissue damage.
- Adhesion molecules on PMNs play a role in their recruitment and activation.
Purpose of the Study:
- To investigate the role of neutrophils (PMNs) in liver injury during endotoxin shock.
- To determine the involvement of PMN-dependent adhesion molecules, specifically CD11/CD18 integrins, in this process.
- To elucidate the mechanisms by which PMNs contribute to liver damage and oxidant stress.
Main Methods:
- Induction of experimental hepatitis in male ICR mice using galactosamine and Salmonella abortus equi endotoxin.
- Quantification of PMN accumulation in the liver.
- Measurement of plasma alanine aminotransferase (ALT) as an indicator of liver injury.
- Assessment of plasma glutathione disulfide (GSSG) as a marker of extracellular oxidant stress.
- Administration of monoclonal antibodies against CD11b, CD18, and CD11a subunits of integrins to evaluate their effects.
Main Results:
- PMN infiltration into the liver significantly increased post-treatment.
- Plasma ALT levels and GSSG formation rose substantially at 9 hours, indicating liver injury and oxidant stress.
- Monoclonal antibodies targeting CD11b and CD18 subunits of the CD11/CD18 integrin family markedly reduced PMN accumulation, liver injury, and GSSG levels.
- Antibodies against CD11a and control antibodies showed no significant effect.
Conclusions:
- Neutrophils (PMNs) are actively involved in the pathogenesis of galactosamine and endotoxin-induced liver injury.
- The accumulation of PMNs, subsequent oxidant stress, and tissue damage in this experimental hepatitis model are, at least in part, dependent on the CD11b/CD18 (Mac-1) integrin.
- Targeting CD11b/CD18 adhesion molecules represents a potential therapeutic strategy for mitigating liver injury in endotoxin shock.