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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H930    most recent 00732.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mink, S. N Articles by Light, R. B. PubMed PubMed Citation Articles by Mink, S. N Articles by Light, R. B.

Lysozyme, a mediator of sepsis that intrinsically generates hydrogen peroxide to cause cardiovascular dysfunction

Departments of ¹Medicine, ²Pharmacology and Therapeutics, and ³Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; and ⁴Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, Mexico

Submitted 14 July 2008 ; accepted in final form 17 June 2009

In septic shock, cardiovascular collapse is caused by the release of inflammatory mediators. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression and arterial vasodilation that develop in canine models of septic shock. To cause vasodilation, Lzm-S generates hydrogen peroxide (H₂O₂) that activates the smooth muscle soluble guanylate cyclase (sGC) pathway, although the mechanism of H₂O₂ generation is not known. To cause myocardial depression, Lzm-S binds to the endocardial endothelium, resulting in the formation of nitric oxide (NO) and subsequent activation of myocardial sGC, although the initial signaling event is not clear. In this study, we examined whether the myocardial depression produced by Lzm-S was also caused by the generation of H₂O₂ and whether Lzm-S could intrinsically generate H₂O₂ as has been described for other protein types. In a canine ventricular trabecular preparation, we found that the peroxidizing agent Aspergillus niger catalase, that would breakdown H₂O₂, prevented Lzm-S- induced decrease in contraction. We also found that compound I, a species of catalase formed during H₂O₂ metabolism, could contribute to the NO generation caused by Lzm-S. In tissue-free experiments, we used a fluorometric assay (Ultra Amplex red H₂O₂ assay) and electrochemical sensor techniques, respectively, to measure H₂O₂ generation. We found that Lzm-S could generate H₂O₂ and, furthermore, that this generation could be attenuated by the singlet oxygen quencher sodium azide. This study shows that Lzm-S, a mediator of sepsis, is able to intrinsically generate H₂O₂. Moreover, this generation may activate H₂O₂-dependent pathways leading to cardiovascular collapse in septic shock.

reactive oxygen species; catalase; compound I; septic shock; myocardial depression