Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

• DOI: 10.1097/ccm.0b013e3182186d27
• Publication Date: 2011-03-25T20:05:17Z
• Authors: Nazima Pathan; Joanne L. Franklin; Hariklia Elefther...; Victoria J. Wright; Cheryl A. Hemingway; Simon J. Waddell; Michael Griffiths; Jayne L. Dennis; David A. Relman; Sian E. Harding; Michael Levin
• Keywords: Proinflammatory cytokine

Myocardial failure, leading to inotrope-unresponsive shock, is the predominant cause of death in meningococcal and other forms septic shock. Proinflammatory cytokines released shock are known have myocardial depressant effects. We previously showed that interleukin 6 a major factor children with septicemia. In current study, we aimed investigate mechanisms by which induces failure sepsis identify potential novel therapeutic targets.Laboratory-based study.University hospital laboratories.Children clinical diagnosis shock.We studied 6-induced signaling events, both vitro using isolated rat ventricular cardiac myocytes as model contractility whole blood from sepsis.None.We demonstrated involvement Janus kinase 2, phosphatidylinositol 3-kinase, Akt, p38 mitogen-activated protein negative inotropy myocytes. Inhibition not only reversed depression human myocytes, but restored inotrope responsiveness. Cardiomyocytes transduced dominant-negative no depression. To vivo, profiled global RNA expression patterns peripheral Transcripts for genes mapping pathway significantly altered levels abundance high proportion this affected.Our findings demonstrate an integral role 6-mediated contractile dysfunction insensitivity. Dysregulation septicemia suggests may be important target therapies reverse patients who responsive inotropic support.