Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 83, Issue -, Pages 31-40Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.02.024
Keywords
Lipopolysaccharide; Nitric oxide; Mitochondria; Adrenal insufficiency; Hydrogen sulfide
Funding
- Major State Basic Research Program of China [2013CB967404]
- National Natural Science Foundation of China [31171120, 31271270, 31371164]
- New Outstanding Young Scholar Program of Shanghai Health Bureau [XYQ2011045]
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We have recently demonstrated that lipopolysaccharide (LPS) causes mitochondrial oxidative stress and dysfunction in adrenal glands, thereby leading to adrenocortical insufficiency. Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) leads to mitochondrial damage in various tissues, the present study aims to investigate whether NO contributes to mitochondrial oxidative stress in adrenal cortex and adrenocortical insufficiency during endotoxemia. Systemic administration of LPS increased iNOS expression and NO production in adrenal glands of mice. The specific iNOS inhibitor 1400 W significantly attenuated the LPS-induced mitochondrial superoxide production and dysfunction in adrenal glands, and reversed the LPS-induced adrenocortical hyporesponsiveness to adrenocorticotropic hormone (ACTH). In contrast, administration of the NO donor sodium nitroprusside (SNP) led to mitochondrial oxidative stress and dysfunction in adrenal glands, which resulted in a blunted corticosterone response to ACTH. Using double immunofluorescence staining for iNOS with the vascular endothelial cell marker CD31 or the macrophage marker CD68, we found that increased iNOS expression was found in vascular endothelial cells and macrophages, but not adrenocortical cells in the adrenal gland during endotoxemia. Administration of the hydrogen sulfide (H2S) donor GYY4137 inhibited NO production and reversed LPS-induced adrenocortical hyporesponsiveness. Our data suggest that overproduction of NO, which is mainly generated by endothelial cells and macrophages during endotoxemia, contributes to mitochondrial oxidative stress in adrenocortical cells and subsequently leads to adrenal insufficiency. (C) 2015 Elsevier Inc. All rights reserved.
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