Effect of interferon gamma on intrahepatic haemodynamics of the cirrhotic rat liver

Abstract

Sublethal injury of the liver with carbon tetrachloride (CCl4) induces the modulation of hepatic stellate cells to their myofibroblast (MFB) phenotype. Pretreatment or concomitant treatment with interferon gamma (IFNgamma) has been shown to inhibit this phenomenon. The aim of this study was to investigate the influence of IFNgamma treatment (50000 IU s.c. each day for 5 days) in rats with an established cirrhosis. Cirrhosis was induced with nine doses of CCl4. Comparison of biopsies before and after treatment with IFNgamma showed that the number of MFB present, identified by their alpha-smooth muscle actin immunoreactivity, was markedly reduced. Pressure-flow curves were constructed in isolated perfused liver preparations from IFNgamma-treated and saline-treated cirrhotic rats and analysed to obtain the extrapolated zero-flow intercept (Po, an index of hepatic vascular distensibility) and the vasodilator-induced change in resistance at a flow rate of 1 mL/min per g (deltaR1, an indication of the level of intrinsic vascular tone). In IFNgamma-treated rats, portal venous pressure measured in vivo was significantly reduced compared with controls (11.9+/-1.2 vs 16.0+/-0.5 mmHg, P< 0.05), Po was lower (2.03+/-0.18 vs 2.87+/-0.32 mmHg, P<0.05) and deltaR1 was decreased (0.39+/-0.15 vs 1.02+/-0.19 mmHg/mL per min per g, P< 0.05). The findings indicate that treatment with IFNgamma is effective in reducing MFB density in established CCl4-cirrhosis in the rat and results in a marked improvement in intrahepatic haemodynamics.

Cirrose experimental induzida pela inalação de tetracloreto de carbono: adaptação da técnica e avaliação da peroxidação lipídica

“…Algumas citocinas já foram relacionadas ao controle da expressão dos miofibroblastos. Assim, agem inibindo-o, tais como o interferongama, interferon-alfa, fator de crescimento hepatocitário e interleucina-10, ou ativando-o, como ocorre com o fator de crescimento tumoralbeta (TGF-beta) e com o fator de necrose tumoral-alfa (TNF-alfa) (9,11,13,14,19) . O grau de fibrose e o nível de estresse oxidativo têm sido relacionados na literatura através de várias técnicas de mensuração de peroxidação lipídica.…”

Assessment of therapeutic benefit of antiviral therapy in chronic hepatitis C: is hepatic venous pressure gradient a better end point?

“…Studies have shown that a sustained biochemical or virological response is associated with a significant decrease in inflammation and more importantly in fibrosis. [6][7][8][9] Furthermore, Shiffman and colleagues 10 showed that one third of patients who had no biochemical response after interferon therapy achieved similar improvement in hepatic histology to those patients with biochemical response. There are also other data to support the finding that the histological response may be partly independent of biochemical and virological effects of interferon monotherapy, and that continuing treatment for long periods in biochemical nonresponders may improve both grading and staging of liver histology.…”

Intrasplenic transplantation of syngenic hepatocytes modified by IFN-gamma gene ameliorates hepatic fibrosis in rats

“…Studies in animal models [16,25, 341 and human subjects [3, 291 have suggested that recombinant IFN-y may retard the progression of fibrosis, or even reverse already established fibrosis, in livers and other organs. Accordingly, in our experiment, the continuous release of IFN-y by genetically modified hepatocytes reduced the pace of liver cirrhosis, based on both morphological assessment and quantification of the collagen content in livers.…”

“…In vitro, IFN-y suppresses the proliferation of hepatic stellate cells (Ito cells) [15], inhibits their transformation to myofibroblasts, and thus reduces the production of collagen fibers [5]. In various animal models of liver cirrhosis, treatment with IFN-y not only prevents the development of liver cirrhosis [ 1, 1 1,25, 33, 341, but also improves fibrosis in established cirrhosis by reducing the production of procollagen types I, 111 and IV in livers [16,301. The anti-fibrogenic activities are associated with decreased hydroxyproline content, reduced density of myofibroblasts, and enhanced expression of interstitial collagenase (MMPl/MMP13) [8].…”