Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide-dependent mechanisms

Abstract

Hydrogen sulfide (HS) is an endogenous gasotransmitter that has vasodilatory properties. It may be a novel therapy for intestinal ischemia-reperfusion (I/R) injury. We hypothesized that ) HS would improve postischemic survival, mesenteric perfusion, mucosal injury, and inflammation compared with vehicle and ) the benefits of HS would be mediated through endothelial nitric oxide. C57BL/6J wild-type and endothelial nitric oxide synthase knockout (eNOS KO) mice were anesthetized, and a midline laparotomy was performed. Intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using laser Doppler. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery. Following ischemia, the clamp was removed, and the intestines were allowed to recover. Either sodium hydrosulfide (2 nmol/kg or 2 µmol/kg NaHS) in PBS vehicle or vehicle only was injected into the peritoneum. Animals were allowed to recover and were assessed for mesenteric perfusion, mucosal injury, and intestinal cytokines. values< 0.05 were significant. HS improved mesenteric perfusion and mucosal injury scores following I/R injury. However, in the setting of eNOS ablation, there was no improvement in these parameters with HS therapy. Application of HS also resulted in lower levels of intestinal cytokine production following I/R. Intraperitoneal HS therapy can improve mesenteric perfusion, intestinal mucosal injury, and intestinal inflammation following I/R. The benefits of HS appear to be mediated through endothelial nitric oxide-dependent pathways. HS is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear whether HS works through nitric oxide-dependent pathways in the intestine. We appreciate that HS was able to improve postischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of HS appear to be mediated through endothelial nitric oxide-dependent pathways.

Hydrogen Sulfide Donor GYY4137 Acts Through Endothelial Nitric Oxide to Protect Intestine in Murine Models of Necrotizing Enterocolitis and Intestinal Ischemia

“…While it is clear that ischemic insult alone does not result in NEC, further investigation into the salvage effects of H 2 S can be bolstered by evaluation of treatment of intestinal ischemia reperfusion (I/R) injury, a much more exact and reproducible model. Previous work has shown that sodium hydrosulfide (NaHS), a H 2 S salt, is protective against intestinal I/R injury in adult mice [10], and similar benefits have been demonstrated in experimental NEC with other hydrogen sulfide donors [11].…”

“…In an intestinal I/R model, the benefit conferred by the NaHS was shown to be dependent on endothelial nitric oxide [10]. Endothelial cells constitutively express the enzyme endothelial nitric oxide synthase (eNOS), which produces the gasotransmitter nitric oxide (NO) [12].…”

Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide

“…NaHS, a donor for H 2 S, significantly attenuates pulmonary iNOS activation in ovalbumin-treated rats (Chen et al, 2009). Moreover, H 2 S is found to act as an anti-inflammatory agent contributing to gastrointestinal mucosal defense through NO-dependent pathway (Jensen et al, 2017). In cardiovascular system, vasodilation is impaired and endothelial H 2 S content is decreased in vessels from obese mice, this may be attributed to the increased iNOS activity in proinflammatory macrophages (Candela et al, 2017).…”

Exogenous Hydrogen Sulfide Alleviates-Induced Intracellular Inflammation in HepG2 Cells

“…Inflammation plays a significant role in inducing liver injury and driving the progression of NAFLD [12]. Numerous reported evi-dences have highlighted the anti-inflammation properties of endogenous H 2 S in the liver, kidney, small intestine, pancreas, lung, brain tissues and immune cells [11,[13][14][15][16][17][18]. Here, we investigated for the first time the anti-inflammation properties of H 2 S in an independent setting in PA-induced HepG2 cells.…”