title: Lysozyme, a mediator of sepsis that intrinsically generates hydrogen peroxide to cause cardiovascular dysfunction.
abstract: 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 (H(2)O(2)) that activates the smooth muscle soluble guanylate cyclase (sGC) pathway, although the mechanism of H(2)O(2) 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 H(2)O(2) and whether Lzm-S could intrinsically generate H(2)O(2) 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 H(2)O(2), prevented Lzm-S- induced decrease in contraction. We also found that compound I, a species of catalase formed during H(2)O(2) metabolism, could contribute to the NO generation caused by Lzm-S. In tissue-free experiments, we used a fluorometric assay (Ultra Amplex red H(2)O(2) assay) and electrochemical sensor techniques, respectively, to measure H(2)O(2) generation. We found that Lzm-S could generate H(2)O(2) 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 H(2)O(2). Moreover, this generation may activate H(2)O(2)-dependent pathways leading to cardiovascular collapse in septic shock.
authors: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. minksn@cc.umanitoba.ca
authors: Steven N
authors: SN
authors: Mink
authors: Hans
authors: H
authors: Jacobs
authors: Zhao-Qin
authors: ZQ
authors: Cheng
authors: Krika
authors: K
authors: Kasian
authors: Luis E
authors: LE
authors: Santos-Martinez
authors: R Bruce
authors: RB
authors: Light
mesh_terms: D000818:Animals; D001234:Aspergillus niger / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000276:immunology / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009113:Muramidase / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; D009113:Muramidase