It is noticeable that CO

It is noticeable that CO as well as H. pylori suppresses apoptosis while it induces autophagy in AGS cells. The differential effects of CO on the activation of transcription factors responsible for regulating expression of apoptosis- and autophagy-related genes merit further investigation. In conclusion, this study presents compelling evidence that H. pylori induces Nrf2 activation through generation of ROS, leading to upregulated expression of HO-1. CO, a by-product of HO-1, induces autophagy while it suppresses the apoptosis (Fig. 7). The induction of autophagy is considered as a cellular defence mechanism by which gastric epithelial RVX-208 damaged by H. pylori-induced oxidative stress are eliminated.
Conflict of interest
Acknowledgements This work was supported by a Global Core Research Center grant from the National Research Foundation, Republic of Korea (No. 2011-0030001).
Introduction Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that degrade heme to carbon monoxide (CO), biliverdin/bilirubin, and free iron. HO-1, the inducible form of HO, is induced by a variety of stimuli, such as endotoxin and cytokines. HO-1 overexpression by pharmacological agents exerts beneficial effects in ALI animal models, as evidenced by preserved lung function and prolonged survival [1,2]. Moreover, HO-1 and its product CO possess potent immunomodulatory properties through the regulation of pro-inflammatory pathways in ALI [3,4]. Hydrogen sulfide (H2S) is a biological gasotransmitter and exhibits various physiological functions, including cytoprotection, antioxidant function, and anti-inflammation. H2S has been demonstrated to protect against sepsis and ALI via inflammation inhibition [5]. However, some studies reported that H2S exacerbates sepsis and ALI due to its pro-inflammatory role [6,7]. It's likely that H2S dose-dependently exerts wide spectrum of effects on inflammation, low and physiological sulfide levels are anti-inflammatory while high sulfide concentrations are pro-inflammatory. GYY4137 [morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate] is a slow-releasing H2S donor and releases H2S over a period of hours. It has been shown that GYY4137 provides low sulfide concentrations and inhibits inflammation in septic rats [8,9].
Materials and methods
Results
Discussion In the current study, we carefully explored the potential effects of GYY4137 in treating ALI and its anti-inflammatory properties in macrophages. GYY4137 elicited conspicuous protection against LPS-induced lung injury in mice. GYY4137 treatment reduced lung injury score, restricted neutrophil infiltration in the lung. Furthermore, GYY4137 inhibited cytokine production, COX-2 and iNOS expression and NF-κB activation, and increased HO-1 protein expression and enzymatic activity. Importantly, SnPP reversed the above-described effects of GYY4137. Meantime, H2S levels in the BALF and supernatant were both increased by GYY4137 but not GYY4137(-) related to the LPS group (Supplementary Fig.1). Inflammatory cells count in the BALF reflects extravasation. Neutrophils are the predominant inflammatory cells in the BALF from ALI patients and play an important role in the development of ALI [13]. Excessive activation of neutrophils can directly induce endothelial injury and destruct the basement membrane, resulting in vascular leakage and eventually lung edema [13]. Furthermore, the abatement of neutrophils obviously attenuates the severity of ALI in animal models [14]. The intrapulmonary instillation of LPS in rodents has been accepted as a clinically relevant model of ALI [15]. In our study, i.t. exposure of mice to LPS resulted in a massive recruitment of inflammatory cells. GYY4137 treatment inhibited the increase in the number of total cells and neutrophils in BALF. Likewise, MPO activity, a marker of neutrophil influx into tissue and directly proportional to the neutrophil number in the tissue, was markedly increased by LPS challenge. The LPS-induced increase in MPO activity was significantly attenuated by GYY4137 treatment. These results indicate that GYY4137 played a potent anti-inflammatory role in LPS-induced ALI in mice.