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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H994    most recent 01044.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yang, M. Articles by Rui, T. Search for Related Content PubMed PubMed Citation Articles by Yang, M. Articles by Rui, T.

Important role of p38 MAP kinase/NF-B signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype

¹Center for Critical Illness Research, Lawson Health Research Institute, ²Critical Care Medicine, London Health Science Center, and ³Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada

Submitted 7 September 2007 ; accepted in final form 11 December 2007

Septic plasma can convert murine cardiac myocytes to a proinflammatory phenotype. These myocytes 1) have increased nuclear levels of nuclear factor-B (NF-B), 2) release CXC chemokines, and 3) promote polymorphonuclear neutrophil (PMN) transendothelial migration. The purpose of the present study was to evaluate the role of the mitogen-activated protein (MAP) kinases [p38 MAP kinase, extracellular signal-regulated kinase (ERK) 1/2, and c-Jun NH₂-terminal kinase (JNK)] as upstream intracellular signaling components involved in this phenomenon. Feces-induced peritonitis (FIP) was employed as a model of sepsis. In vitro, cardiac myocytes were treated with plasma (20%) obtained 6 h after either sham (saline) or FIP procedures. Myocyte supernatants were used for 1) detection of the CXC chemokines (enzyme-linked immunosorbent assay) and 2) assessment of their ability to promote PMN transendothelial migration. In vivo, myocardial PMN accumulation was assessed by measuring myeloperoxidase (MPO) activity and function (dF/dt and heart work). Treatment of cardiac myocytes with septic plasma activated p38 MAP kinase and ERK1/2, but not JNK. Blockade approaches (inhibitors or small-interference RNA) indicated that only p38 MAP kinase played a role in the conversion of the myocytes to a proinflammatory phenotype. Time course studies indicated that phosphorylation of p38 MAP kinase preceded the phosphorylation of NF-B p65. Inhibition of p38 MAP kinase (SB-202190) blocked both NF-B p65 phosphorylation and NF-B nuclear translocation. Confirmatory studies in vivo indicated that FIP resulted in an increase in myocardial MPO activity and dysfunction, events reversed by the inhibitor of p38 MAP kinase. Collectively, these data indicate that the cardiomyocyte p38 MAP kinase/NF-B signaling pathway plays an important role in the sepsis-induced conversion of myocytes to a proinflammatory phenotype.

mice; chemokines; polymorphonuclear transendothelial migration; myocardial contractility; mitogen-activated protein kinase; nuclear factor-B