Platelets and alpha-naphthylisothiocyanate-induced liver injury.
Administration of alpha-naphthylisothiocyanate (ANIT) to rats results in periportal cholangiolitic hepatopathy. Inflammation is a hallmark of the liver injury, and expression of toxicity is dependent on blood neutrophils. The role of other cellular mediators of inflammation in ANIT-induced hepatic insult is unknown. We hypothesized that platelets participate in the expression of ANIT hepatotoxicity. To test this, circulating platelets were decreased by administration of anti-rat platelet serum (PAb) prior to treatment of rats with ANIT. The PAb treatment regimen effectively reduced circulating thrombocytes over the course of the experiment. Twenty-four hours after oral ANIT administration, rats were euthanized and liver injury was estimated by increases in serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities. Cholestasis was assessed by measurement of serum total bilirubin concentration and bile flow. Reduction in platelet numbers was associated with attenuation of the increases in plasma ALT activity and bilirubin concentration seen after ANIT administration. However, PAb treatment did not attenuate the increase in plasma GGT, a marker of biliary epithelial cell injury. ANIT-induced changes in platelet function were assessed by evaluating platelet aggregation responses in platelet-rich plasma from rats treated with ANIT in vivo. ANIT treatment modestly decreased ex vivo platelet aggregation in response to ADP and collagen stimuli. To address further the role of platelet-derived cyclooxygenase products in ANIT hepatotoxicity, rats were treated with aspirin or ibuprofen. Neither pretreatment ameliorated ANIT-induced hepatic insult. These results suggest that platelets contribute to the expression of ANIT-induced liver injury, but they do not appear to act through the production of cyclooxygenase metabolites.
Bailie
M B
MB
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Pearson
J M
JM
Lappin
P B
PB
Killam
A L
AL
Roth
R A
RA
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D007052:Ibuprofen / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D051381:Rats; D017207:Rats, Sprague-Dawley
D007106:Immune Sera; D015058:1-Naphthylisothiocyanate; D001241:Aspirin; D007052:Ibuprofen