Abstract
Stimulation by a number of conditions, including infection, cytokines, mechanical injury, and hypoxia, can upregulate inducible nitric oxide synthase (iNOS) in hepatocytes. We observed that exposure to hypergravity significantly upregulated the transcription of the hepatic iNOS gene. The aim of this study was to confirm our preliminary data, and to further investigate the distribution of the iNOS protein in the livers of mice exposed to hypergravity. ICR mice were exposed to +3 Gz for 1 h. We investigated the time course of change in the iNOS expression. Hepatic iNOS mRNA expression progressively increased in centrifuged mice from 0 to 12 h, and then decreased rapidly by 18 h. iNOS mRNA levels in the livers of centrifuged mice was significantly higher at 3, 6, and 12 h than in uncentrifuged control mice. The pattern of iNOS protein expression paralleled that of the mRNA expression. At 0 and 1 h, weak cytoplasmic iNOS immunoreactivity was found in some hepatocytes surrounding terminal hepatic venules. It was noted that at 6 h there was an increase in the number of perivenular hepatocytes with moderate to strong cytoplasmic immunoreactivity. The number of iNOS-positive hepatocytes was maximally increased at 12 h. The majority of positively stained cells showed a strong intensity of iNOS expression. The expression levels of iNOS mRNA and protein were significantly increased in the livers of mice exposed to hypergravity. These results suggest that exposure to hypergravity significantly upregulates iNOS at both transcriptional and translational levels.
Highlights
The generation of nitric oxide (NO) from L-arginine and molecular oxygen has been proposed to mediate or modulate cellular damage in several organs, including the brain, kidneys, and liver [1,2,3,4,5]
We evaluated the levels of inducible nitric oxide synthase (iNOS) mRNA and protein expression in the livers of mice exposed to hypergravity
We observed further increases in iNOS mRNA expression, which rose significantly at 3 h, reached a maximum at 12 h, and disappeared shortly afterward. These results are consistent with those of our preliminary study [20]. iNOS protein expression showed a trend similar to that observed for the levels of iNOS mRNA
Summary
The generation of nitric oxide (NO) from L-arginine and molecular oxygen has been proposed to mediate or modulate cellular damage in several organs, including the brain, kidneys, and liver [1,2,3,4,5]. Unlike endothelial NOS and neuronal NOS, iNOS is not expressed constitutively, but is expressed in most cell types given the appropriate stimulatory conditions, which include infection, cytokines, mechanical injury, and hypoxia [6]. INOS is not thought to be expressed constitutively. It is readily upregulated in the liver under a number of disease conditions, including ischemia-reperfusion injury, hepatic fibrosis, cirrhosis and regeneration [7,8,9,10,11,12]. INOS is upregulated in vitro in hepatocytes and Kupffer cells in response to endotoxins and cytokines alone or in combination [13,14,15,16,17]. The availability of specific antibodies directed against iNOS has prompted attempts to understand their cellular distribution in the liver, and how that may affect the pathogenesis of liver dysfunction [13,18,19]
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