Experimental model of cirrhosis in rabbits exposed to carbon tetrachloride by inhalation

Orthotopic hepatic transplantation is the most diffused surgical treatment used when attempting to substitute an irreversibly damaged liver. However, this practice faces two main problems. Firstly, surgeons need to explant the organ from the donor who is a just deceased human being, with all the implications involved. Secondly, the host patient must be rendered immunologically tolerant to the graft, through pharmacological suppression. Some hepatic alterations allow a structural and functional compensation by means of an autotransplant, but liver cirrhosis, which is widely diffused in humans and easily produced in experimental animals, has not yet been treated with this technique. This research was undertaken with the aim of procuring hepatic cirrhosis in a medium-sized animal--the rabbit--exposed for some months to CCl4 vapours. Preliminary experiments were performed in order to shorten the challenge period by means of liver induction. This approach was unsuccessful because of the natural susceptibility of this species, which was heightened by the barbiturate administration (0.05% sodium phenobarbital in drinking water, for one week). However, induction, rendered impossible the survival after carbon tetrachloride given orally (125 microliters/kg body weight) or by inhalation (1000 ppm for 2 hours). Finally, CCl4 was administered to normal rabbits by inhalation at the initial concentration of 100 ppm, for 2 hours twice a week. The level of the hepatotoxin was subsequently raised stepwise, according to the body weight curve, up to the maximum of 600 ppm by week 23. At the fourth week of intoxication, the metabolic activity of liver microsomes appeared severely depressed, as shown by the 300% increase of hexobarbital sleeping time. The observation of the surface of liver in situ, performed through an explorative laparatomy, showed initial but clear signs of hepatic fibrosis. At sacrifice, after six or ten months of cirrhogenic treatment, the histopathology examination of the liver demonstrated severe and massive cirrhosis, respectively for the two different steps. This experimental schedule appears to be suitable for producing hepatic cirrhosis in a medium-sized animal, which could be used as a model for pioneering attempts of liver autotransplantation. Furthermore, we point out two important aspects of these results. First, the poison has been inhaled by the experimental animals as it generally happens for humans in the environment. Second, the ratio between the length of exposure versus the life span of rabbits--6 months and 8 years, respectively--parallels that reported for human cirrhosis due to halogenated hydrocarbons--5 or 10 years versus 60 or 80 years.