Human neutrophils employ chlorine gas as an oxidant during phagocytosis

被引:222
|
作者
Hazen, SL
Hsu, FF
Mueller, DM
Crowley, JR
Heinecke, JW
机构
[1] WASHINGTON UNIV, SCH MED, DEPT MED, ST LOUIS, MO 63110 USA
[2] WASHINGTON UNIV, SCH MED, DEPT MOL BIOL & PHARMACOL, ST LOUIS, MO 63110 USA
来源
JOURNAL OF CLINICAL INVESTIGATION | 1996年 / 98卷 / 06期
关键词
myeloperoxidase; inflammation; oxidation; hypochlorous acid; atherosclerosis;
D O I
10.1172/JCI118914
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Reactive oxidants generated by phagocytes are of central importance in host defenses, tumor surveillance, and inflammation. One important pathway involves the generation of potent halogenating agents by the myeloperoxidase-hydrogen peroxide-chloride system. The chlorinating intermediate in these reactions is generally believed to be HOCl or its conjugate base, ClO-. However, HOCl is also in equilibrium with Cl-2, raising the possibility that Cl-2 executes oxidation/halogenation reactions that have previously been attributed to HOCl/ClO-. In this study gas chromatography-mass spectrometric analysis of head space gas revealed that the complete myeloperoxidase-hydrogen peroxide-chloride system generated Cl-2. In vitro studies demonstrated that chlorination of the aromatic ring of free L-tyrosine was mediated by Cl-2 and not by HOCl/ClO-. Thus, 3-chlorotyrosine serves as a specific marker for Cl-2-dependent oxidation of free L-tyrosine. Phagocytosis of L-tyrosine encapsulated in immunoglobulin- and complement-coated sheep red blood cells resulted in the generation of 3-chlorotyrosine. Moreover, activation of human neutrophils adherent to a L-tyrosine coated glass surface also stimulated 3-chlorotyrosine formation. Thus, in two independent models of phagocytosis human neutrophils convert L-tyrosine to 3-chlorotyrosine, indicating that a Cl-2-like oxidant is generated in the phagolysosome. In both models, synthesis of 3-chlorotyrosine was inhibited by heme poisons and the peroxide scavenger catalase, implicating the myeloperoxidase-hydrogen peroxide system in the reaction. Collectively, these results demonstrate that myeloperoxidase generates Cl-2 and that human neutrophils use an oxidant with characteristics identical to those of Cl-2 during phagocytosis. Moreover, our observations suggest that phagocytes exploit the chlorinating properties of Cl-2 to execute oxidative and cytotoxic reactions at sites of inflammation and vascular disease.
引用
收藏
页码:1283 / 1289
页数:7
相关论文
共 50 条