Regenerative and fibrotic pathways in canine liver disease

Abstract

Liver diseases occur quite frequently in dogs; the overall incidence in dogs has been estimated around 1-2% of the clinical cases. Most liver diseases are, like in humans, chronic and occur through chronic inflammation due to different causes. In all cases the on-going liver cell damage leads to a reduction of the functional liver cell mass and progressive deposition of fibrous tissue in the liver. These two phenomena, atrophy and fibrosis, are two sides of one medal and go hand in hand to cause fatal liver dysfunction in the end stage. The large regenerative capacity of the liver is lost in the course of chronic disease. There is convincing evidence that the two main counteracting factors, Hepatocyte Growth Factor (HGF) and Transforming Growth Factor-β1 (TGF-β1), determine the outcome of liver disease. HGF is the principal factor stimulating the liver to grow and regenerate and suppresses fibrosis and apoptosis. In contrast, TGF-β1 induces formation of excessive fibrous tissue and a reduction of the regenerative capacity together with stimulation of cell death. The findings with respect to the crucial counteracting effects of HGF and TGF-β1 in liver growth, regeneration and fibrosis, have stimulated researchers to investigate the potential of administering HGF to experimental animals given hepatotoxic or fibrogenic drugs. Administration of HGF completely prevented or, when given afterwards, reversed toxic effects. Even in cases of chronic damage with already formed disruption of the normal micro-architecture of the liver, fibrosis and atrophy (cirrhosis), this phenomenon could largely be reversed. Furthermore, the normal fatal course of peracute fulminant hepatitis (severe acute hepatic sepsis or toxicity) could be prevented in experimental animals. The few studies in dogs indicate that the above findings also apply to this species. Interestingly, one of the first reports of a very potent liver regeneration stimulating factor (now known as HGF) was found in dogs. Extrapolation for the above mentioned rodent models to human medicine has not been achieved. The use of novel therapeutic approaches in dogs presented at the veterinary clinic could be seen as a much more relevant animal model for the translation to human clinical medicine. For instance, HGF treatment during normally life-threatening hepatic diseases could cause a revolution in the treatment of liver diseases (in both man and dog). Therapeutic intervention could be achieved by the addition of the HGF-glycoprotein itself. Alternatively, and in line with the concept that the clinical outcome is determined by the balance between HGF and TGF-β1, gene therapy approaches resulting in blocking the effects of TGF-β1 have been similarly effective, at least in chronic disease models. Taken together, the central theme of this thesis involves several aims. The first aim is to describe the regulatory roles of Hepatocyte Growth Factor (HGF) and Transforming Growth Factor-β1 (TGF-β1), via the respective receptors c-MET and TGF-β1 receptors type II and I in growth, regeneration, and formation of fibrosis in a variety of liver diseases. Second, development of therapeutic tools based on the above insights to treat liver diseases characterized by inadequate growth or atrophy with fibrosis and/or cirrhosis, especially by influencing the balance between HGF and TGF-β1 in the liver. Finally, initial evaluation of the effects of such therapeutic tools.