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Ischemia-Reperfusion of Rat Myocardium Activates Nuclear Factor-&kgr;B and Induces Neutrophil Infiltration Via Lipopolysaccharide-Induced CXC Chemokine

BackgroundMechanisms by which neutrophils are attracted to the myocardium in ischemia/reperfusion are not fully defined. Lipopolysaccharide-induced CXC chemokine (LIX), cytokine-induced neutrophil chemoattractant (KC), and macrophage inflammatory protein-2 (MIP-2) are rodent chemokines with potent neutrophil-chemotactic activity. The goals of the present study were to evaluate the roles of these chemokines in a rat model of ischemia/reperfusion and to examine the mechanisms of chemokine induction by oxidative stress and cytokines in cultured cardiomyocytes. Methods and ResultsMale Wistar-Kyoto rats underwent 45 minutes of ligation of the left anterior descending coronary artery, followed by reperfusion for various periods. Compared with sham-operated controls, myocardium from reperfused animals had higher levels of free radicals, increased neutrophil infiltration evidenced histologically and by elevated myeloperoxidase activity, and increased nuclear factor (NF)-&kgr;B DNA binding activity. Ischemia-reperfusion also induced the expression of interleukin-1&bgr;, tumor necrosis factor (TNF)-&agr;, LIX, KC, and MIP-2 mRNA and protein. LIX expression was localized to resident myocardial cells, whereas KC and MIP-2 were expressed only in infiltrating inflammatory cells. Neutralization of LIX inhibited 79% of neutrophil infiltration into previously ischemic myocardium. In contrast, neutralization of KC and MIP-2 reduced neutrophil infiltration by only 28% and 37%, respectively. In cultured cardiomyocytes, LIX expression was induced by oxidative stress or TNF-&agr; and was blocked by the NF-&kgr;B inhibitor pyrrolidinedithiocarbamate. ConclusionsLIX is expressed by resident myocardial cells during ischemia-reperfusion and is induced in cultured cardiomyocytes by oxidative stress or TNF-&agr; via NF-&kgr;B activation. Although KC and MIP-2 are expressed by inflammatory cells infiltrating the myocardium during reperfusion after ischemia, neutrophil recruitment to reperfused rat myocardium is mainly due to cardiomyocyte expression of LIX.