Hepatic Collagenase Activity During Carbon Tetrachloride Induced Fibrosis

Hepatic Collagenase Activity During Carbon Tetrachloride InducedFibrosis. Lindblad, W.J. and Fuller, G.C. (1983). Fundam. Appl.Toxicol. 3:34-40. The contribution of collagen degradation,as measured by collagenase activity, to the accumulation ofcollagen during hepatotoxic fibrogenesis was examined usinga carbon tetrachloride rat model. Both active and inactive enzymeforms were determined with the inactive form quantitated followingactivation by limited trypsin digestion of the liver homogenate.The rate of collagen biosynthesis was monitored by quantitatinghepatic prolyl hydroxylase activity and accumulation of collagen.In one study CCl₄ was administered twice weekly, i.p. (0.2 mL,33% v/v in light mineral oil) for sixteen weeks, with animalssacrificed every two weeks. Histologic examination of liversections and serum alanine transaminase levels indicated a progressivenecrosis and fibrosis which was confirmed by the increase inhepatic hydroxyproline content from 0.303 to 4.84 µg/mgwet wt. tissue. Prolyl hydroxylase activity increased in a timedependent manner to a maximum of 3.7 x control. This increasewas accompanied by a large increase in both active collagenase(15.0–40.8 mU/mg protein) and latent collagenase activity(69.8–191.7 mU/mg protein). These increases were maintainedthrough the transition to irreversible fibrosis. The increasein active collagenase activity was positively correlated withcollagen content. A second short term CCl₄ treatment study confirmeda transient alteration in the active to latent collagenase ratioearly in the fibrotic process. These results demonstrate thedynamic changes in hepatic collagenase levels and indicate thatthe fibrotic lesion is not dependent on decreased collagenaselevels for collagen accumulation.