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Depletion of neutrophils and modulation of Kupffer cell function in allyl alcohol-induced hepatotoxicity
1Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
Abstract:
The roles of neutrophils (PMNs) and Kupffer cells in hepatotoxicity caused by allyl alcohol in rats in vivo were examined. To test the involvement of PMNs in the response to allyl alcohol, the number of circulating PMNs was reduced to < 500/microliter by treatment with immunoglobulin (Ig) isolated from serum of rabbits treated with rat PMNs (anti-PMN Ig). Rats received anti-PMN Ig or control Ig 6 h before and 6 h after administration of allyl alcohol (40 mg/kg, i.p.). Hepatotoxicity was assessed 18 h after allyl alcohol administration. In rats pretreated with control Ig, treatment with allyl alcohol resulted in hepatotoxicity as evidenced by an increase in the activity of alanine aminotransferase (ALT) in serum. Neutropenia did not attenuate hepatic injury caused by allyl alcohol. Leukopenia induced by pretreatment with cyclophosphamide also did not influence the hepatotoxic response to allyl alcohol. To inhibit the function of Kupffer cells, animals were treated with gadolinium chloride (GdCl3; 10 mg/kg, i.v.) 24 h before administration of allyl alcohol. This dose of GdCl3 decreased in situ clearance of colloidal carbon by 64%. Despite the inhibition of Kupffer cell function, ALT activity in serum was not different in allyl alcohol-treated rats pretreated with GdCl3 and those pretreated with saline vehicle. Histopathologic evaluation of the livers confirmed a lack of protective effect of GdCl3. These results suggest that neither neutrophils nor Kupffer cells play a major role in liver injury due to allyl alcohol.
Insights
This study investigated neutrophils and Kupffer cells in allyl alcohol-induced liver injury in rats. Results indicate neither neutrophils nor Kupffer cells play a significant role in this hepatotoxicity.
Area of Science:
- Toxicology
- Hepatology
- Immunology
Background:
- Allyl alcohol is a known hepatotoxin.
- The specific cellular mechanisms of allyl alcohol-induced liver injury are not fully understood.
- Neutrophils (PMNs) and Kupffer cells are key immune cells in the liver that may contribute to drug-induced liver injury.
Purpose of the Study:
- To determine the role of neutrophils (PMNs) in allyl alcohol-induced hepatotoxicity in rats.
- To investigate the involvement of Kupffer cells in allyl alcohol-induced liver injury.
Main Methods:
- Neutropenia was induced using anti-PMN Ig, and Kupffer cell function was inhibited with gadolinium chloride (GdCl3).
- Hepatotoxicity was assessed by measuring serum alanine aminotransferase (ALT) levels and histopathological examination.
- Rats were administered allyl alcohol (40 mg/kg) and treatments were given at specific time points before and after intoxication.
Main Results:
- Neutropenia did not attenuate the hepatic injury caused by allyl alcohol.
- Inhibition of Kupffer cell function with GdCl3 did not protect against allyl alcohol-induced liver damage.
- Histopathological evaluation confirmed the lack of a protective effect from GdCl3 treatment.
Conclusions:
- Neither neutrophils nor Kupffer cells appear to play a major role in the acute liver injury induced by allyl alcohol in rats.
- These findings suggest alternative mechanisms may be responsible for allyl alcohol hepatotoxicity.