Ischemia-Reperfusion of Rat Myocardium Activates Nuclear Factor-κB and Induces Neutrophil Infiltration Via Lipopolysaccharide-Induced CXC Chemokine

Abstract

Background-Mechanisms 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 Results-Male 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)-B DNA binding activity. Ischemia-reperfusion also induced the expression of interleukin-1␤, tumor necrosis factor (TNF)-␣, 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-␣ and was blocked by the NF-B inhibitor pyrrolidinedithiocarbamate. Conclusions-LIX is expressed by resident myocardial cells during ischemia-reperfusion and is induced in cultured cardiomyocytes by oxidative stress or TNF-␣ via NF-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.

An IL-17F/A Heterodimer Protein Is Produced by Mouse Th17 Cells and Induces Airway Neutrophil Recruitment

“…were not significantly modulated in any of the treatment groups, CXCL5 (LIX), another potent neutrophil chemoattractant (34,35), was significantly reduced by the IL-17A-specific Ab to concentrations similar to those of control mice. Abs specific for IL-17F or IL-22 did not alter CXCL5 concentrations.…”

Tissue-Specific Effects of the Nuclear Factor κB Subunit p50 on Myocardial Ischemia-Reperfusion Injury

“…29 Chronic exposure of proinflammatory cytokines can shift the ratio of transcriptionally active heterodimers to the transcriptionally inactive p50 homodimers, which can act as negative feedback mechanism to prevent excessive production of proinflammatory proteins and may thereby account for the increased expression of proinflammatory proteins in the p50 KO. However, because those factors aggravate the ischemic response in other models, 30 they cannot account for cardioprotection in p50 KOs.…”

The immune system and cardiac repair

“…In rodents several ELR positive CXC chemokines, including GRO-α/KC, Macrophage Inflammatory Protein (MIP)-2 and LipopolysaccharideInduced CXC chemokine (LIX), induce neutrophil chemotaxis and activation through binding to their main receptor, CXCR2. Experiments in a rat model of infarction demonstrated that, although KC and MIP-2 are upregulated in the injured heart, neutrophil recruitment in reperfused rat infarcts appeared to be mainly due to expression of LIX [107]. Deficiency of CXCR2, the main receptor for the ELR-containing CXC chemokines, resulted in significantly decreased inflammatory leukocyte recruitment in murine infarcts, suggesting a crucial role for these chemokines in inflammatory cell infiltration [108].…”