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Published online before print June 28, 2007

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(Journal of Leukocyte Biology. 2007;82:894-905.)
© 2007 by Society for Leukocyte Biology

Endogenous hydrogen sulfide regulates leukocyte trafficking in cecal ligation and puncture-induced sepsis

Huili Zhang^*, Liang Zhi^*, Shabbir M. Moochhala, Philip Keith Moore^* and Madhav Bhatia^*,1

^* Department of Pharmacology, National University of Singapore, Singapore; and
DSO National Laboratories, Singapore

¹ Correspondence: Cardiovascular Biology Research Programme, Department of Pharmacology, Centre for Life Sciences, National University of Singapore, 28 Medical Drive, #03-02, Singapore 117456. E-mail: mbhatia{at}nus.edu.sg

Hydrogen sulfide (H₂S) is recognized increasingly as a proinflammatory mediator in various inflammatory conditions. Here, we have investigated the role of H₂S in regulating expression of some endothelial adhesion molecules and recruitment of leukocytes to inflamed sites in sepsis. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with saline (i.p.), DL-propargylglycine (PAG; 50 mg/kg, i.p.), an inhibitor of H₂S formation or NaHS (10 mg/kg, i.p.), an H₂S donor. PAG was administered 1 h before or after the induction of sepsis, and NaHS was given at the same time of CLP. Using intravital microcopy, we found that in sepsis, prophylactic and therapeutic administration of PAG reduced leukocyte rolling and adherence significantly in mesenteric venules coupled with decreased mRNA and protein levels of adhesion molecules (ICAM-1, P-selectin, and E-selectin) in lung and liver. In contrast, injection of NaHS up-regulated leukocyte rolling and attachment significantly, as well as tissue levels of adhesion molecules in sepsis. Conversely, normal mice were given NaHS (10 mg/kg, i.p.) to induce lung inflammation, with or without NF-B inhibitor BAY 11-7082 pretreatment. NaHS treatment enhanced the level of adhesion molecules and neutrophil infiltration in lung. These alterations were reversed by pretreatment with BAY 11-7082. Moreover, expression of CXCR2 in neutrophils obtained from H₂S-treated mice was up-regulated significantly, leading to an obvious elevation in MIP-2-directed migration of neutrophils. Therefore, H₂S acts as an important endogenous regulator of leukocyte activation and trafficking during an inflammatory response.

Key Words: inflammation • adhesion molecules • leukocyte–endothelial interaction • DL-propargylglycine

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