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Hydrogen Sulfide Up-Regulates Substance P in Polymicrobial Sepsis-Associated Lung Injury¹

Huili Zhang^*, Akhil Hegde^*, Siaw Wei Ng^*, Sharmila Adhikari^*, Shabbir M. Moochhala and Madhav Bhatia^2,*

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

Hydrogen sulfide (H₂S) has been shown to induce the activation of neurogenic inflammation especially in normal airways and urinary bladder. However, whether endogenous H₂S would regulate sepsis-associated lung inflammation via substance P (SP) and its receptors remains unknown. Therefore, the aim of the study was to investigate the effect of H₂S on the pulmonary level of SP in cecal ligation and puncture (CLP)-induced sepsis and its relevance to lung injury. Male Swiss mice or male preprotachykinin-A gene knockout (PPT-A^–/–) mice and their wild-type (PPT-A^+/+) mice were subjected to CLP-induced sepsis. DL-propargylglycine (50 mg/kg i.p.), an inhibitor of H₂S formation was administered either 1 h before or 1 h after the induction of sepsis, while NaHS, an H₂S donor, was given at the same time as CLP. L703606, an inhibitor of the neurokinin-1 receptor was given 30 min before CLP. DL-propargylglycine pretreatment or posttreatment significantly decreased the PPT-A gene expression and the production of SP in lung whereas administration of NaHS resulted in a further rise in the pulmonary level of SP in sepsis. PPT-A gene deletion and pretreatment with L703606 prevented H₂S from aggravating lung inflammation. In addition, septic mice genetically deficient in PPT-A gene or pretreated with L703606 did not exhibit further increase in lung permeability after injection of NaHS. The present findings show for the first time that in sepsis, H₂S up-regulates the generation of SP, which contributes to lung inflammation and lung injury mainly via activation of the neurokinin-1 receptor.

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 (Grant R-184-000-094-305) and Office of Life Sciences Cardiovascular Biology Program (Grant R-184-000-074-712), National University of Singapore.

² 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, No. 03-02, Singapore 117456. E-mail address: mbhatia{at}nus.edu.sg

³ Abbreviations used in this paper: SP, substance P; NK1R, neurokinin-1 receptor; H₂S, hydrogen sulfide; CSE, cystathionine -lyase; CLP, cecal ligation and puncture; PAG, DL-propargylglycine; NK2R, neurokinin-2 receptor; MPO, myeloperoxidase; TRPV1, transient receptor potential vanilloid receptor 1.

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