Regeneration and Fibrosis in Canine Hepatitis and Cirrhosis
World Small Animal Veterinary Association World Congress Proceedings, 2006
Jan Rothuizen
Professor of Internal Medicine, Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, University Utrecht

Chronic hepatitis is characterized by hepatocellular apoptosis or necrosis, inflammation, and fibrosis. Fibrosis is the major factor causing morbidity and mortality due to the development of cirrhosis. We have studied different forms of hepatitis: Acute Hepatitis (AH) without fibrosis, Chronic Hepatitis (CH), and cirrhosis (CIRR), including Lobular Dissecting Hepatitis (LDH). The last disease is a specific form of cirrhosis with severe fibrosis and complete disruption of the lobular architecture.

It has already been established that a transient increase of transforming growth factor β1 (TGF-β1) in the liver promotes fibrosis with the formation of extracellular matrix (ECM) components and suppresses hepatocyte proliferation. The major components of the ECM are interstitial collagens (types I and III), membrane collagen (type IV), and non-collagenous glycoproteins, such as laminin and fibronectin.

We analyzed liver fibrosis using several molecular and biochemical techniques (Q-PCR, Western blotting, and semi-quantitative immunohistochemistry on ECM proteins).

Prolonged overexpression of TGF-β1 suppresses cell proliferation, is pro-apoptotic, and induces a deposition of ECM proteins, resulting in fibrosis in major organs such as the liver.

In fibrotic diseases (CH, LDH, and CIRR) the TGF-β1 pathway was activated. There was an increase in mRNA levels of the TGF-β1 ligand and the two receptors. uPA, the activator of TGF-β1, was expressed at a higher level. Western blotting confirmed increased TGF-β1 in these diseases. In summary, increased levels of TGF-β1 signaling may very well explain the activation of Smad-2 and subsequently the formation of collagens.

Immunostaining against collagen I and III on normal liver tissues showed normal staining of the collagens in portal tracts, around the hepatic veins, as well as in the parasinoidal space (particularly centrolobular). The corresponding results of mRNA levels and immunostaining in LDH can be explained by the rapid clinical course of the disease in LDH. In CCl4-induced rodent models of liver fibrosis, TGF-β1 and procollagen mRNAs were increased, including procollagen I, III, and IV.

The mechanisms underlying progressive fibrosis are unknown, but hypoxia is a known fibrogenic stimulus. On the other hand, it is conceivable that increased collagen deposition leads to reduced oxygen levels in the surrounding tissue and consequently up regulates HIF-1α. Indeed, the two major fibrotic diseases, LDH and CIRR, clearly showed an induction of HIF-1α mRNA levels of 3- and 7-fold, respectively.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Jan Rothuizen
Faculty of Veterinary Medicine
Utrecht University
Utrecht, The Netherlands

MAIN : Hepatology : Canine Hepatitis & Cirrhosis
Powered By VIN