1. Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia
- Author
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Peng, Tianqing, Lu, Xiangru, Lei, Ming, Moe, Gordon W., and Feng, Qingping
- Subjects
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MITOGENS , *PROTEIN kinases , *ENDOTOXINS , *TUMOR necrosis factors - Abstract
Objectives: 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-α) 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-α 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-α mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-α mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF-α production in the myocardium and blocking p38 MAPK activation inhibited TNF-α expression in response to LPS. Pre-treatment of SB202190 or a TNF-α 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). Conclusion: p38 MAPK activation represents an important mechanism leading to myocardial TNF-α production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia. [Copyright &y& Elsevier]
- Published
- 2003
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