H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Resveratrol alleviates endotoxemia-associated adrenal insufficiency by suppressing oxidative/nitrative stress.

We have recently demonstrated that endotoxin causes oxidative stress and overproduction of nitric oxide in adrenal glands, thereby leading to adrenocortical insufficiency. The aim of this study is to investigate the effects of resveratrol, a natural plant polyphenol with anti-oxidant and anti-nitrative properties, on endotoxemia-associated adrenocortical insufficiency. Resveratrol was administered immediately before injection of lipopolysaccharide (LPS). Twenty four hours later, the adrenocorticotropic hormone (ACTH) stimulation tests was been performed to measure the plasma corticosterone level and the adrenal gland tissues were collected for histopathologic examination, and determination of malondialdehyde (MDA), total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) and peroxynitrite production. Treatment with resveratrol significantly inhibited endotoxemia-induced iNOS expression, NO production, and peroxynitrite formation and also attenuated LPS-induced oxidative stress in the adrenal gland, as evidenced by the decrease of pro-oxidant biomarker (MDA), and the increases of anti-oxidant biomarkers (T-AOC, CAT and SOD activity). H&E staining demonstrated that administration of LPS resulted in increased into the adrenal gland. H&E-stained sections of adrenal glands demonstrated signs of leukocyte infiltration and hemorrhage during endotoxemia, which were significantly improved by resveratrol treatment. In addition, resveratrol reversed the LPS-induced downregulation of ACTH receptor and silent information regulator 1 (SIRT1) in adrenal gland, as well as adrenocortical hyporesponsiveness to ACTH. Resveratrol exerts protective effects against endotoxemia-associated adrenocortical insufficiency by suppressing oxidative/nitrative stress. These findings support the potential for resveratrol as a possible pharmacological agent to improve adrenocortical insufficiency resulting from oxidative/nitrative damage.

Treatment of fenestrated vertebrobasilar junction-related aneurysms with endovascular techniques.

Fenestrated vertebrobasilar junction-related aneurysms (fVBJ-AN) are uncommon and endovascular management strategies have become the first options for the treatment of these lesions. This clinical study aimed to report our experience in the endovascular management of these lesions and to review the literature. We retrospectively reviewed 10 consecutive patients harboring 12 fVBJ-AN between January 2007 and December 2014. The demographic, angiographic and clinical data were reviewed. Additionally, a literature review was performed. Endovascular management strategies were successfully applied in all 10 patients. Post-procedural angiograms indicated total occlusion in eight (66.7%) aneurysms, a residual neck in one (8.3%) aneurysm, and three residual aneurysms (25%). No procedure-related complications were observed. Follow-up angiograms were obtained in eight patients and revealed nine occluded aneurysms and one improved aneurysm; two patients were lost to angiographic follow-up. Clinical follow-ups were obtained in all patients (until July 2015), and the modified Rankin Scale scores at 69.5months (range 17-101months) of follow-up were 0 in eight patients and 1 in two patients. Endovascular management strategies provided a high occlusion rate and an acceptable complication rate and are thus efficacious in the treatment of fVBJ-AN. Further studies are necessary to validate the utility of these treatments due to the low incidence of fVBJ-AN.

Overproduction of nitric oxide by endothelial cells and macrophages contributes to mitochondrial oxidative stress in adrenocortical cells and adrenal insufficiency during endotoxemia.

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.

CBS and CSE are critical for maintenance of mitochondrial function and glucocorticoid production in adrenal cortex.

AIMS: Mitochondria are known to play a central role in adrenocortical steroidogenesis. Recently, hydrogen sulfide (H2S), a gaseous transmitter endogenously produced by cystathionine-ß-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. RESULTS: 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. INNOVATION: 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. CONCLUSIONS: 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.

Protective effect of resveratrol against endotoxemia-induced lung injury involves the reduction of oxidative/nitrative stress.

BACKGROUND: Resveratrol, a natural plant polyphenol, has received increasing attention because its varied bioactivities, including the inhibition of tumorigenesis, lipid modification and calorie-restriction. We aimed to investigate the effect of resveratrol on oxidative/nitrative stress in endotoxemia-associated acute lung injury. METHODS: Mice were injected with lipopolysaccharide (LPS, 5 mg/kg, ip). Resveratrol at a dose of 0.3 mg/kg was administered alone or immediately before injection of LPS. Twenty four hours later, lung tissues were collected for histopathologic examination, and determination of malondialdehyde (MDA), H2O2, reduced/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) and peroxynitrite production. RESULTS: Resveratrol treatment improves histopathological changes in the lung during endotoxemia. Increased oxidative stress in endotoxemic lung was reversed by resveratrol treatment, as evidenced by the decreases of pro-oxidant biomarker (MDA and H2O2), and the increases of anti-oxidant biomarkers (GSH/GSSG ratio, T-AOC, CAT and SOD activity). Treatment with resveratrol inhibited endotoxemia-induced iNOS expression and NO production. Moreover, peroxynitrite formation in endotoxemic lung was significantly attenuated after resveratrol treatment. CONCLUSIONS: Resveratrol exerts protective effects against acute endotoxemia-associated lung injury. These beneficial effects may be due to both the anti-oxidant and anti-nitrative properties of resveratrol. These findings support the potential for resveratrol as a possible pharmacological agent to reduce acute lung injury resulting from oxidative/nitrative damage.