IMMUNOHISTOCHEMICAL LOCALIZATION OF HEPATIC NITRIC-OXIDE SYNTHASE IN NORMAL AND TRANSGENIC SICKLE-CELL MICE - THE EFFECT OF HYPOXIA

Nitric oxide (NO) generated from L-arginine and molecular oxygen by ni tric oxide synthase (NOS) has been shown to influence hepatocellular f unction and pathology in response to ischemia and certain hepatotoxins . In the present study, we examined the liver of a transgenic line of sickle cell mice for hepatocellular injury and localization of two iso forms of NOS, the endothelial constitutively expressed isoform (EcNOS) and the inducible isoform (iNOS) by immunohistochemistry, Diffuse exp ression of EcNOS was observed in hepatocytes of control and sickle cel l animals maintained under room air conditions, In contrast, iNOS was observed only in the sickle cell mice, well-localized to hepatocytes s urrounding the central veins of the lobules. When normal mice were exp osed to hypoxic conditions for 4 to 5 days, iNOS immunostaining appear ed de novo in a patchy distribution throughout the liver lobules. In t he sickle cell mice, hypoxia appeared to increase the subjective inten sity of pericentral staining of iNOS. Liver histology was normal in th e sickle cell mice maintained under room air conditions, but showed mu ltifocal areas of necrosis when sickling was exacerbated by chronic hy poxic conditions, However, a pericentral zone of preserved architectur e was present, corresponding to the region of iNOS staining, We postul ate that pericentral induction of iNOS under ambient conditions occurs in transgenic sickle cell mice in response to particularly intense hy poxic conditions near the central veins of the liver. Increases in NO synthesis may occur in this region, which would serve to protect these cells from ischemic damage either directly or by maintaining blood fl ow. These findings could be relevant to liver pathophysiology in patie nts with sickle cell disease. (C) 1996 by The American Society of Hema tology.