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Endogenous Hydrogen Sulfide Regulates Inflammatory Response by Activating the ERK Pathway in Polymicrobial Sepsis¹

Huili Zhang^2,*, Shabbir M. Moochhala and Madhav Bhatia^3,*

^* Department of Pharmacology, National University of Singapore, Singapore; and Centre for Biomedical Science, Defence Medical and Environmental Research Institute, Defence Science Organization, Singapore

Hydrogen sulfide (H₂S) up-regulates inflammatory response in several inflammatory diseases. However, to date, little is known about the molecular mechanism by which H₂S provokes the inflammatory response in sepsis. Thus, the aim of this study was to investigate the signaling pathway underlying the proinflammatory role of H₂S in cecal ligation and puncture (CLP)-induced sepsis. Male Swiss mice were subjected to CLP and treated with DL-propargylglycine (PAG; 50 mg/kg i.p., an inhibitor of H₂S formation), NaHS (10 mg/kg, i.p., an H₂S donor), or saline. PAG was administered 1 h before CLP, whereas NaHS was given at the time of CLP. CLP-induced sepsis resulted in a time-dependent increase in the synthesis of endogenous H₂S. Maximum phosphorylation of ERK1/2 and degradation of IB in lung and liver were observed 4 h after CLP. Inhibition of H₂S formation by PAG significantly reduced the phosphorylation of ERK1/2 in lung and liver 4 h after CLP, coupled with decreased degradation of IB and activation of NF-B. In contrast, injection of NaHS significantly enhanced the activation of ERK1/2 in lung and liver, therefore leading to a further rise in tissue NF-B activity. As a result, pretreatment with PAG significantly reduced the production of cytokines and chemokines in sepsis, whereas exogenous H₂S greatly increased it. In addition, pretreatment with PD98059, an inhibitor of ERK kinase (MEK-1), significantly prevented NaHS from aggravating systemic inflammation in sepsis. In conclusion, the present study shows for the first time that H₂S may regulate systemic inflammatory response in sepsis via ERK pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Biomedical Research Council (Grants R-184-000-094-305 and R-184-000-092-305) and Office of Life Sciences Cardiovascular Biology Program (Grant R-184-000-074-712), National University of Singapore.

² Current address: Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, China.

³ Address correspondence and reprint requests to Dr. Madhav Bhatia, Cardiovascular Biology Research Programme, Department of Pharmacology, Centre for Life Sciences, National University of Singapore, 28 Medical Drive, #03-02, Singapore 117456. E-mail address: mbhatia{at}nus.edu.sg

⁴ Abbreviations used in this paper: H₂S, hydrogen sulfide; ALT, alanine aminotransferase; CBS, cystathionine β-synthase; CLP, cecal ligation and puncture; CSE, cystathionine -lyase; HPRT, hypoxanthine-guanine phosphoribosyltransferase; MPO, myeloperoxidase; PAG, DL-propargylglycine; PKA, protein kinase A.