Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-alpha

This study examined the hypothesis that burn trauma promotes cardiac myocyt e secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-a lpha and produces cardiac contractile dysfunction via the p38 mitogen-activ ated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into f our groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats giv en the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postbur n), 3) rats given third-degree burns over 40% total body surface area and t reated with vehicle (1 ml of saline) plus lactated Ringer solution for resu scitation (4 ml.kg(-1).percent burn(-1)), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at sev eral times postburn to examine p38 MAPK activity (by Western blot analysis or in vitro kinase assay); myocardial function and myocyte secretion of TNF -alpha were examined at 24-h postburn. These studies showed significant act ivation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myo cyte secretion of TNF-alpha. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-alpha, and prevented burn-mediated cardiac deficit s. These data suggest p38 MAPK activation is one aspect of the signaling ca scade that culminates in postburn secretion of TNF-alpha and contributes to postburn cardiac dysfunction.