Cytoprotective Effects of Hydrogen Sulfide in Novel Rat Models of Non-Erosive Esophagitis

Abstract

Non-erosive esophagitis is a chronic inflammatory condition of the esophagus and is a form of gastroesophageal reflux disease. There are limited treatment options for non-erosive esophagitis, and it often progresses to Barrett’s esophagus and esophageal carcinoma. Hydrogen sulfide has been demonstrated to be a critical mediator of gastric and intestinal mucosal protection and repair. However, roles for H2S in esophageal mucosal defence, inflammation and responses to injury have not been reported. We therefore examined the effects of endogenous and exogenous H2S in rat models of non-erosive esophagitis. Mild- and moderate-severity non-erosive esophagitis was induced in rats through supplementation of drinking water with fructose, plus or minus exposure to water-immersion stress. The effects of inhibitors of H2S synthesis or of an H2S donor on severity of esophagitis was then examined, along with changes in serum levels of a pro- and an anti-inflammatory cytokine (IL-17 and IL-10, respectively). Exposure to water-immersion stress after consumption of the fructose-supplemented water for 28 days resulted in submucosal esophageal edema and neutrophil infiltration and the development of lesions in the muscular lamina and basal cell hyperplasia. Inhibition of H2S synthesis resulted in significant exacerbation of inflammation and injury. Serum levels of IL-17 were significantly elevated, while serum IL-10 levels were reduced. Treatment with an H2S donor significantly reduced the severity of esophageal injury and inflammation and normalized the serum cytokine levels. The rat models used in this study provide novel tools for studying non-erosive esophagitis with a range of severity. H2S contributes significantly to mucosal defence in the esophagus, and H2S donors may have therapeutic value in treating esophageal inflammation and injury.

Hydrogen sulfide from a NaHS source attenuates dextran sulfate sodium (DSS)-induced inflammation via inhibiting nuclear factor-κB

“…Xu et al (2015) reported that pre-treatment with NaHS ameliorates high glucoseinduced inflammation in H9c2 cardiac cells, evidenced by the inhibition of IL-1β, IL-6, and TNF-α expression. Furthermore, treatment with an H 2 S donor in a rat model of non-erosive esophagitis markedly alleviated the inflammatory response and regulated serum IL-17 concentration (Zayachkivska et al, 2014). Thus, we speculate that H 2 S may serve as an anti-inflammatory agent in DSS-induced inflammation in vivo and in vitro.…”

Functional and Molecular Insights of Hydrogen Sulfide Signaling and Protein Sulfhydration

“…This was supported by studies where it was shown that H2S treatment attenuates adherence of leukocytes to the vascular endothelium and impairs extravasation of leukocytes; however Inhibition of endogenous H2S rescued the phenotype [107, 108]. Recent studies related to sub-dermal inflammation, H2S treatment provides a protective function by suppressing leukocyte infiltration and edema formation [109]. Moreover, several groups have shown that H2S suppress the expression of cell adhesion molecules on both the endothelium (e.g., intercellular adhesion molecule (ICAM)-1 and P-selectin) and on the leukocyte (lymphocyte function-associated antigen (LFA)-1) [110, 111].…”

H2S-releasing drugs: Anti-inflammatory, cytoprotective and chemopreventative potential

“…H2S also increases phagocytosis of bacteria by macrophages, and promotes a shift of phenotype of macrophages to the "M2", pro-resolution state [14]. H2S donors can also reduce inflammation by reducing the expression of a number of proinflammatory cytokines (e.g., tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, interferon (IFN)-Y but sparing of expression of the pro-inflammatory cytokine, IL-10 [10,11,15]. Inhibition of pro-inflammatory cytokine expression most likely occurs by suppression of nuclear factor ĸB (NFĸB) activity by H2S [16].…”

“…IL-10-deficient mice exhibit impaired H2S synthesis in the colon (and these mice can spontaneously develop colitis) [7,17]. Administration of H2S donors increases IL-10 expression [7,15], while administration of IL-10 to the IL-10-deficient mice restored normal colonic H2S synthesis [7].…”