The effect of interferon γ on hepatic haemodynamics

See article on page 1058 In this issue of this journal, Grossman et al. report that interferon gamma (IFNy) affects the haemodynamics of the cirrhotic liver. Interferon y improved hepatic haemodynamics by reducing intrinsic vascular tone.' Although IFNy was reported to inactivate stellate cells and, consequently, reduce collagen the relationship between IFNy and hepatic microcirculation had not been studied until now. Interferon y increases expression of inducible nitric oxide synthase (iNOS) in Kupffer cells and stellate cell^.^,^ In combination with lipopolysaccharide, IFNy also increased production of nitric oxide (NO) from hepatocytes.6 Furthermore, lipopolysaccharide induces NO following production of IFNy from endothelial cells and macrophages.' Nitric oxide was also derived from hepatocytes in coculture with Kupffer cells.8 Nitric oxide is also known as endothelial-derived relaxing factor (EDRF) and is a strong vasodilator.' In livers perfused with alcohol, an increase in portal vein pressure due to endothelin-1 was inhibited by NO;" this led to relaxation of stellate cells.5 Taken together, these studies suggest that IFNy induces relaxation of stellate cells via NO, resulting in an increase in hepatic haemodynamics. Several problems remained to be resolved concerning the effects of IFNy and the role of stellate cells on hepatic haemodynamics after treatment with IFNy. In the paper by Grossman et al., IFNy was given to rats after administration of CCl,. This experimental design was different from previous experiments which showed the inhibition of activation of stellate cells with IFNy. For example, Baroni et al. administered IFNy simultaneously with dimethylnitrosamineY2 while Rockey and Chung administered IFNy prior to the addition of CCl,.' These experiments indicated that IFNy inhibited activation of stellate cells; however, Grossman's experiment seems to reflect induction of a reverse transformation of activated stellate cells to the inactivated phenotype, a big difference in terms of inactivation of stellate cells. Although IFNIX was reported to inhibit activation of stellate cells," so far no information has been reported about transformation of activated stellate cells to the inactivated phenotype by IFNy. Further investigations are required to assess the amount or staining of a-smooth muscle actin, the amount of vitamin A and the expression of extracellular matrix in cirrhotic liver after administration of IFNy. An electron microscopic examination should also be performed to characterize the quiescent stellate cells after IFNy treatment. An effect of IFNy on liver function tests, such as alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase, was not shown in the Grossman paper. If there is no effect of IFNy on liver tests, the ability to administer IFNy to a damaged liver is questionable. Furthermore, the actual involvement of myofibroblasts (activated stellate cells) located at the sinusoids in lowering the vascular resistance is still unclear, since the relaxation of the terminal portal vein at the presinusoidal wall was not investigated. Observations with in vivo microscopy might show a change of the diameter of sinusoids with IFNy. In addition, the influence of IFNy on the adhesion of polymorphonuclear leucocytes to the sinusoidal endothelium and on aggregation of platelets in sinusoids is unknown. These factors have also been reported to disturb the hepatic microcirculation." The expression of adhesion molecules, such as intercellular adhesion molecule-1 , on the sinusoidal endothelium after treatmentwith1FNyhasnotyetbeenstudied.Vasoactive substances change the size of fenestrae (sieve plates) located on the sinusoidal end0the1ium.l~ Although it is supposed that an increase in the size of the fenestrae reduces vascular resistance, no study using IFNy has been carried out. Moreover, the effect of IFNy on secretion of NO, eicosanoids, endothelin1 and neurotransmitters, such as vasoactive intestinal peptide or substance P, was not investigated. In summary, many points remain to be clarified concerning the detailed mechanism of the IFNyinduced decrease in vascular resistance found in cirrhosis, with respect to the activation and deactivation of stellate cells.These could include degradation of the extracellular matrixbymatrixmetalloproteinaseandthe tissueinhibitor of metalloproteinase.