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B signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype
1 Center for Critical Illness Research, Lawson Health Research Institute, London, Canada; Department of Medical Biophysics, University of Western Ontario, London, Canada
2 Critical Care Medicine, London Health Science Center, London, Canada; Center for Critical Illness Research, Lawson Health Research Institute, London, Canada
3 Center for Critical Illness Research, Lawson Health Research Institute, London, Canada; Critical Care Medicine, London Health Science Center, London, Canada; Department of Medical Biophysics, University of Western Ontario, London, Canada
* To whom correspondence should be addressed. E-mail: trui{at}uwo.ca.
Septic plasma can convert murine cardiac myocytes to a proinflammatory phenotype. These myocytes 1) have increased nuclear levels of NF
B, 2) release CXC chemokines and 3) promote PMN transendothelial migration. The purpose of the present study was to evaluate the role of the MAP kinases (p38 MAP kinase, ERK1/2, and 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 hrs after either sham (saline) or FIP procedures. Myocyte supernatants were used for 1) detection of the CXC chemokines (ELISA) and 2) assessment of their ability to promote PMN transendothelial migration. In vivo, myocardial PMN accumulation was assessed by measuring 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 siRNA) 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 NFB p65. Inhibition of p38 MAP kinase (SB202190) blocked both NFB p65 phosphorylation and NFB 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 cardiomyocyte p38 MAP kinase/NFB signaling pathway plays an important role in the sepsis-induced conversion of myocytes to a proinflammatory phenotype.
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