Release of TNF-α during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers
- 作者：Gilles ; Stefanie ; Zahler ; Stefan ; Welsch ; Ulrich ; Sommerhoff ; Christian P. ; Becker ; Bernhard F.
- 关键词：Cytokines ; Free radicals ; Ischemia ; Reperfusion ; TNF-α ; tumor necrosis factor-α ; TACE ; TNF-α ; -converting enzyme ; ADAM ; a disintegrin and metalloproteinase ; MMP ; matrix metalloproteinase ; TAPI-2 ; TNF-α ; protease inhibitor ; HONHCOCH2<
- 刊名：Cardiovascular Research
- 出版年：2003
- 期刊代码：48_00086363
- 类别：med
- 出版时间：December 1, 2003
- 卷：60
- 期：3
- 页码：608-616
- 文件大小：619 K
摘要
Objectives: Our study sought to elucidate the role of oxidative stress for shedding of tumor necrosis factor-α (TNF-α) and for activating TNF-α-converting enzyme (TACE). Background: TNF-α, a central inflammatory cytokine, is discussed as one of the mediators of reperfusion injury. Shedding of membrane-bound pro-TNF-α is thought to be largely due to TNF-α-converting enzyme (TACE). Methods: Release of TNF-α and TACE dependency were studied in isolated rat hearts and in the human mast cell line HMC-1. Results: In reperfused hearts, interstitial release of TNF-α occurred in two phases (2–10 and >45 min). It depended on the presence of oxygen during reperfusion and was attenuated by reduced glutathione. Infusion of the oxidants H2O2 or HOCl elicited release in non-ischemic hearts. TNF-α release was inhibited in hearts treated with degranulation inhibitors ketotifen or cromoglycate, suggesting mast cells as major source for myocardial TNF-α. This was confirmed by tissue staining. Post-ischemic release of histamine, however, did not parallel that of TNF-α. Heart tissue contained mainly mature TACE. HMC-1 expressed abundant pro-TACE and cleaved the pro-TNF-α-peptide Ac-SPLAQAVRSSSR-NH2. However, cleavage was nonspecific and only partly inhibited by TACE inhibitor TAPI-2 (10–100 μmol/l), while it was stimulated by H2O2 and HOCl and fully blocked by the nonspecific metalloprotease inhibitor o-phenanthroline. Conclusions: The mechanism underlying TNF-α release from post-ischemic myocardium is oxidation-dependent but largely independent of activation of TACE. Mast cell stabilizers may be useful in preventing TNF-α release during reperfusion.