The regression of
cirrhosis is associated with increased intrahepatic collagenolytic
enzyme activity. We investigated whether
collagenase supplementation via portal vein infusion can retard
cirrhosis development and/or reverse
cirrhosis. In all, 35 rabbits were initially assigned to study. However, because of high surgical mortality and
infection, only 15 animals completed study. Four normal controls (group I) received
olive oil subcutaneously (SC) for 12 weeks followed by
normal saline portal perfusion for 12 weeks. Four (group II) received CCl(4) SC for 6 weeks followed by portal vein
collagenase, 6 mg twice weekly, plus SC CCl(4) for 6 additional weeks and then killed. Four rabbits (group III) received CCl(4) SC for 12 weeks and then 6 mg of
collagenase portally for 12 weeks, while three control rabbits (group IV) received CCl(4) for 12 weeks followed by saline for 12 weeks. After 12 weeks of CCl(4), liver
hydroxyproline content of
collagenase-treated group II (361.1+/-106.6 microg/g) was significantly reduced compared with group III+IV that had not yet received
collagenase (589.0+/-162.9 microg/g; P<0.05). In the main comparison,
hydroxyproline content of
collagenase-treated group III (177.5+/-35.6 microg/g) was significantly decreased compared with saline-treated controls (446.3+/-150.1 microg/g; P<0.01). Further, liver histology showed complete regression of
cirrhosis in the
collagenase-treated animals. No toxicity of liver, kidney, lung, brain or heart was observed histologically.
Anaphylaxis occurred in 2/35 original animals (one fatal). In conclusion, this study provides 'proof of principle' that
collagenase portal administration can retard
cirrhosis development and speed regression of established
cirrhosis in the rabbit CCl(4) model. Potential application to humans is premature, but feasible, if these findings are confirmed in additional animal studies.