gyy-4137 and Endotoxemia

In a previous study, we showed that endogenous hydrogen sulfide (H

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Apoptosis; Corticosterone; Cystathionine beta-Synthase; Cysteine; Endotoxemia; Hydrogen Sulfide; Lipopolysaccharides; Male; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proton-Translocating ATPases; Morpholines; Organothiophosphorus Compounds; Sulfides

Topics: Animals; Apoptosis; Caco-2 Cells; Cell Membrane Permeability; Disease Models, Animal; Electric Impedance; Endotoxemia; Enterocytes; Gastrointestinal Agents; Gene Expression Regulation; Humans; Interferon-gamma; Intestinal Mucosa; Lipopolysaccharides; Male; Mice, Inbred C57BL; Morpholines; Organothiophosphorus Compounds; Protective Agents; Random Allocation; Tight Junction Proteins; Tight Junctions; Tumor Necrosis Factor-alpha

Hydrogen sulfide (H2S), known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI) induced by endotoxemia.. Male ICR mice were divided in six groups: (1) Control group; (2) GYY4137treatment group; (3) L-NAME treatment group; (4) lipopolysaccharide (LPS) treatment group; (5) LPS with GYY4137 treatment group; and (6) LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich) reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting.. GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC) and theactivities of catalase (CAT) and superoxide dismutase (SOD) but decreased a marker of peroxynitrite (ONOO-) action and 3-nitrotyrosine (3-NT) in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL)-6, IL-8, and myeloperoxidase (MPO) and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA), hydrogenperoxide (H2O2) and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio) and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS) expression and nitric oxide (NO) production in the endotoxemia lung.. GYY4137 conferred protection against acute endotoxemia-associated lung injury, which may have beendue to the anti-oxidant, anti-nitrative and anti-inflammatory properties of GYY4137. The present findings warrant further exploration of the clinical applicability of H2S in the prevention and treatment of ALI.

Topics: Acute Lung Injury; Animals; Antioxidants; Endotoxemia; Hydrogen Peroxide; Hydrogen Sulfide; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lung; Male; Malondialdehyde; Mice, Inbred ICR; Morpholines; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrosation; Organothiophosphorus Compounds; Oxidative Stress; Tyrosine

Mitochondria are known to play a central role in adrenocortical steroidogenesis. Recently, hydrogen sulfide (H2S), a gaseous transmitter endogenously produced by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), has been found to improve mitochondrial function. The present study aimed at examining whether CBS and CSE are expressed in adrenal glands, and investigated the role of these enzymes in the maintenance of mitochondrial function and the production of glucocorticoids in adrenocortical cells.. Both CBS and CSE are present in murine adrenocortical cells and account for H2S generation in adrenal glands. Using a combination of both in vivo and in vitro approaches, we demonstrated that either CBS/CSE inhibitors or small interfering RNAs led to mitochondrial oxidative stress and dysfunction, which meanwhile resulted in blunted corticosterone responses to adrenocorticotropic hormone (ACTH). These effects were significantly attenuated by the treatment of H2S donor GYY4137. Lipopolysaccharide (LPS) also caused mitochondrial damage, thereby resulting in adrenal insufficiency. Moreover, LPS inhibited CBS/CSE expression and H2S production in adrenal glands, while H₂S donor GYY4137 protected against LPS-induced mitochondrial damage and hyporesponsiveness to ACTH. Local suppression of CBS or CSE in adrenal glands significantly increased the mortality in endotoxemic mice, which was also improved by GYY4137.. The identification of endogenous H2S generation as critical regulators of adrenocortical responsiveness might result in the development of new therapeutic approaches for the treatment of relative adrenal insufficiency during sepsis.. Endogenous H₂S plays a critical role in the maintenance of mitochondrial function in the adrenal cortex, thereby resulting in an adequate adrenocortical response to ACTH.

Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Corticosterone; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Endotoxemia; Glucocorticoids; Hydrogen Sulfide; Lipopolysaccharides; Mice; Mitochondria; Morpholines; Organothiophosphorus Compounds; Oxidative Stress; RNA, Small Interfering