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Neutrophil depletion protects against liver injury from bacterial endotoxin
J A Hewett1, A E Schultze, S VanCise
1Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
Abstract:
Neutrophil (PMN) infiltration is an early occurrence in the liver after exposure to hepatotoxic doses of endotoxin lipopolysaccharide (LPS). The purpose of this study was to test the hypothesis that PMNs contribute to the pathogenesis of LPS hepatotoxicity. The immunoglobulin fraction from serum of rabbits immunized with rat PMNs (anti-PMN Ig) was administered intravenously to rats 18 and 6 hours before exposure to an hepatotoxic dose of LPS (Escherichia coli 0128:B12). This protocol caused a greater than 95% reduction in circulating PMNs, which was maintained for the duration of the study. The immunoglobulin fraction from nonimmunized rabbits was used as a control (control Ig). Rats pretreated with control Ig exhibited a marked increase in the number of PMNs in the liver 1.5 hours after LPS exposure. This increase in hepatic PMNs was significantly reduced by pretreatment with anti-PMN Ig. Marked elevations in both alanine and aspartate aminotransferase activities (1086 +/- 311 and 880 +/- 183 SF units/ml, respectively) were observed in plasma from control Ig-treated rats 6 hours after intravenous administration of LPS (3.0 mg/kg). The response to LPS was greatly attenuated in animals receiving anti-PMN Ig (145 +/- 111 and 224 +/- 49 SF units/ml alanine and aspartate aminotransferase activities, respectively). Pretreatment of rats with immunoglobulins to rat lymphocytes reduced numbers of circulating lymphocytes but did not afford protection against the hepatotoxic effects of LPS. These results suggest that PMNs contribute to the pathogenesis of LPS hepatotoxicity.
Insights
Neutrophils (PMNs) play a key role in liver damage caused by lipopolysaccharide (LPS). Reducing PMN levels significantly protected rats from LPS-induced liver injury, indicating PMNs contribute to this toxicity.
Area of Science:
- Hepatology
- Immunology
- Toxicology
Background:
- Neutrophil infiltration into the liver is an early event following exposure to hepatotoxic doses of lipopolysaccharide (LPS).
- The precise role of neutrophils in the pathogenesis of LPS-induced liver injury remains to be fully elucidated.
Purpose of the Study:
- To investigate the contribution of neutrophils (PMNs) to the development of liver damage induced by lipopolysaccharide (LPS).
Main Methods:
- Rats were pretreated with an immunoglobulin fraction against rat PMNs (anti-PMN Ig) or control Ig before LPS administration.
- Circulating PMN levels were monitored, and liver injury was assessed by measuring plasma aminotransferase activities.
- The effect of anti-lymphocyte Ig on LPS hepatotoxicity was also evaluated.
Main Results:
- Pretreatment with anti-PMN Ig significantly reduced hepatic PMN infiltration post-LPS exposure.
- Anti-PMN Ig treatment markedly attenuated the elevations in alanine and aspartate aminotransferase activities caused by LPS.
- Control Ig-treated rats showed significant increases in hepatic PMNs and liver enzymes after LPS exposure.
Conclusions:
- Neutrophils (PMNs) are key mediators in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury.
- Targeting PMN infiltration offers a potential therapeutic strategy for mitigating LPS hepatotoxicity.