title: Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia.
abstract: OBJECTIVE
  The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-alpha) expression, cardiac function and survival during acute endotoxemia in mice.
  
  
  METHODS
  Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF-alpha mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.
  
  
  RESULTS
  LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF-alpha mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-alpha mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF-alpha production in the myocardium and blocking p38 MAPK activation inhibited TNF-alpha expression in response to LPS. Pre-treatment of SB202190 or a TNF-alpha antagonist etanercept (2 mg/kg, i.p) significantly reversed LPS-induced LV depression (P<0.05). LPS (20 mg/kg, i.p.) induced 94% mortality in mice within 72 h and pre-treatment with SB202190 and etanercept decreased LPS-induced mortality to 65 and 40%, respectively (P<0.01).
  
  
  CONCLUSIONS
  p38 MAPK activation represents an important mechanism leading to myocardial TNF-alpha production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia.
authors.affiliation: Cardiology Research Laboratory, Lawson Health Research Institute, London Health Science Centre, Department of Medicine, University of Western Ontario, London, Ontario N6A 4G5, Canada.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Moe
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000208:Acute Disease; D000818:Animals; D019446:Endotoxemia / Q000378:metabolism*; D000068800:Etanercept; D007093:Imidazoles / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D012313:RNA / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007093:Imidazoles; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D011725:Pyridines; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068800:Etanercept; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole