Sy. Osei et al., IMMUNOHISTOCHEMICAL LOCALIZATION OF HEPATIC NITRIC-OXIDE SYNTHASE IN NORMAL AND TRANSGENIC SICKLE-CELL MICE - THE EFFECT OF HYPOXIA, Blood, 88(9), 1996, pp. 3583-3588
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.