Madorin W Sean, Rui Tao, Sugimoto Naohito, Handa Osamu, Cepinskas Gediminas, Kvietys Peter R
Vascular Cell Biology Laboratory, Lawson Health Research Institute and the Department of Physiology, University of Western Ontario, London, Ontario, Canada.
Circ Res. 2004 Apr 16;94(7):944-51. doi: 10.1161/01.RES.0000124395.20249.AE. Epub 2004 Feb 26.
Cardiac myocytes isolated from rats with peritonitis (cecal ligation and perforation; CLP) promote PMN transendothelial migration. Herein, we assessed (1) the mechanisms involved in cardiac myocyte activation during peritonitis and (2) the means by which these activated myocytes promote PMN transendothelial migration. Plasma obtained from mice subjected to CLP (septic plasma) activated isolated cardiac myocytes as evidenced by (1) increased nuclear levels of nuclear factor-kappaB (NF-kappaB) and (2) their ability to promote PMN migration across endothelial cell monolayers. Pretreatment of septic plasma with an antibody against tumor necrosis factor-alpha (TNF-alpha), but not interleukin-1beta (IL-1beta), blunted the ability of septic plasma to activate the myocytes. However, septic plasma obtained from TNF-alpha-deficient mice could still activate the myocytes; an effect attenuated by an antibody against IL-1beta. If the myocytes were pretreated with a proteasome inhibitor (MG 132) to prevent NF-kappaB activation, the myocyte-induced PMN transendothelial migration was compromised. The activated myocytes released platelet-activating factor (PAF), and myocyte-induced PMN migration was abrogated by a PAF receptor antagonist (WEB 2086). These myocytes also released the CXC chemokines LIX and KC; an event prevented by MG 132. Antibodies against LIX and KC abrogated the myocyte-induced PMN migration. However, LIX and KC, but not PAF, could promote PMN migration when used at concentrations produced by activated myocytes. These observations indicate that TNF-alpha and IL-1beta are, in part, responsible for the ability of septic plasma to activate cardiac myocytes. The activated myocytes promote PMN transendothelial migration, an effect attributable to LIX and KC, and possibly, PAF.
从患有腹膜炎（盲肠结扎和穿孔；CLP）的大鼠中分离出的心肌细胞可促进中性粒细胞跨内皮迁移。在此，我们评估了（1）腹膜炎期间心肌细胞激活所涉及的机制，以及（2）这些活化的心肌细胞促进中性粒细胞跨内皮迁移的方式。从接受CLP的小鼠获得的血浆（脓毒症血浆）激活了分离的心肌细胞，这表现为：（1）核因子-κB（NF-κB）的核水平升高，以及（2）它们促进中性粒细胞穿过内皮细胞单层迁移的能力。用抗肿瘤坏死因子-α（TNF-α）抗体而非白细胞介素-1β（IL-1β）预处理脓毒症血浆，可减弱脓毒症血浆激活心肌细胞的能力。然而，从TNF-α缺陷小鼠获得的脓毒症血浆仍能激活心肌细胞；抗IL-1β抗体可减弱这种作用。如果用蛋白酶体抑制剂（MG 132）预处理心肌细胞以阻止NF-κB激活，则心肌细胞诱导的中性粒细胞跨内皮迁移会受到影响。活化的心肌细胞释放血小板活化因子（PAF），PAF受体拮抗剂（WEB 2086）可消除心肌细胞诱导的中性粒细胞迁移。这些心肌细胞还释放CXC趋化因子LIX和KC；MG 132可阻止这一过程。抗LIX和KC抗体可消除心肌细胞诱导的中性粒细胞迁移。然而，当以活化心肌细胞产生的浓度使用时，LIX和KC而非PAF可促进中性粒细胞迁移。这些观察结果表明，TNF-α和IL-1β部分负责脓毒症血浆激活心肌细胞的能力。活化的心肌细胞促进中性粒细胞跨内皮迁移，这一作用归因于LIX和KC，可能还有PAF。
