ACUTE-PHASE RESPONSE IN RAT TO CARBON TETRACHLORIDE-AZATHIOPRINE INDUCED CIRRHOSIS AND PARTIAL-HEPATECTOMY OF CIRRHOTIC LIVER

Irreversible liver cirrhosis was induced in rats by supplementing thei r diet with 0.02% azathioprine and intubating them twice a week with c arbon tetrachloride in corn oil. Over a period of 3 mo, intoxicated ra ts showed an atypical acute-phase reaction (APR). The relative concent rations of haptoglobin, beta-lipoprotein, alpha-1-antitrypsin, an unkn own peak ''X,'' and transferrin increased exponentially following a mi ld initial drop, while albumin, C3c + C3, alpha-1-acid glycoprotein, a lpha-1-lipoprotein, and macroglobulin declined continually during the experiment. The accumulated peritoneal fluid was found to contain a si milar spectrum of APR proteins. On the other hand histological examina tion revealed gradual liver damage manifested as a gradual increase in the areas of collagen separating liver cells, and at the end of the e xperiment, severe liver damage was evident with isolated hepatocytes i n a matrix of collagen. The available data point to the disparity that exists between the physical status of hepatocytes and their biochemic al function, which suggests that the remaining metabolically fatigued hepatocytes of the cirrhotic liver continue to biosynthesize and relea se elevated concentrations of some secretable APR proteins and less of others. Changes in the spectrum of APR plasma components during the p rogression of inflammatory or physical lesion remain a valid biochemic al measure of the pathological function of the acutely intoxicated liv er. Partial hepatectomy (PH) of cirrhotic liver displayed a mute APR a nd no regenerative activity of the remnant hepatic tissue, most likely due to the substantial depletion of hepatic DNA and possible chemical damage to DNA of the remaining viable hepatocytes. A possible cause f or the depressed APR to the surgical insult of PH is that-the initial azathioprine-CCl4 intoxication had maximally affected APR gene express ion and a second injury would then elicit minimal further changes in m RNA levels. Thus, in a compounded pathological condition, the initial inflammatory stimulus on various pre-rRNAs, rRNAs, and mRNAs is rate-l imiting to the hepatic biosynthesis and secretion of APR proteins and may not respond linearly, if at all, to a second stimulus.