Evidence against a role for endotoxin in the hepatic encephalopathy of rats with thioacetamide-induced fulminant hepatic failure.
OBJECTIVE
Endotoxin has been proposed to participate in the development of hepatic encephalopathy. However, there is no published data concerning the effects of endotoxin neutralization on the degree of hepatic encephalopathy. The present study investigated the effect of chronic intraperitoneal injection of polymyxin B, a neutralizing antagonist of endotoxin, on hepatic encephalopathy in rats with thioacetamide (TAA)-induced fulminant hepatic failure.


METHODS
Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Two series of rats were designed to compare the effects of low dose (0.1 mg) or high dose (0.2 mg) intraperitoneal polymyxin B administration versus normal saline (NS) on hepatic encephalopathy. The injection was twice daily started from 2 days prior to TAA administration and lasted for 5 days. Severity of encephalopathy was assessed by the counts of motor activity in an Opto-Varimex animal activity meter. Plasma levels of endotoxin and tumor necrosis factor-alpha (an index of liver injury) were measured by Limulus assay and the ELISA method, respectively.


RESULTS
Neutralization of endotoxin by either low dose or high dose polymyxin B administration did not significantly alleviate the degree of hepatic encephalopathy, as represented by the counts of motor activities (P > 0.05). Plasma levels of endotoxin and tumor necrosis factor-alpha were comparable between rats treated with polymyxin B or NS (P > 0.05).


CONCLUSIONS
Our findings do not support the notion that endotoxin plays a major role in the pathogenesis of hepatic encephalopathy in rats with TAA-induced fulminant hepatic failure.
Chen
Chien-Ting
CT
Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Chu
Chi-Jen
CJ
Wang
Teh-Fang
TF
Lu
Rei-Hwa
RH
Lee
Fa-Yauh
FY
Chang
Full-Young
FY
Lin
Han-Chieh
HC
Chan
Che-Chang
CC
Wang
Sun-Sang
SS
Huang
Hui-Chun
HC
Lee
Shou-Dong
SD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005500:Follow-Up Studies; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000150:complications*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011112:Polymyxin B / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013853:Thioacetamide / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D011112:Polymyxin B