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P38 MAPK mediates myocardial proinflammatory cytokine production and endotoxin-induced contractile suppression

Meijing Wang1, Rajakumar Sankula, Ben M Tsai

  • 1Department of Surgery, Section of Cardiothoracic Surgery, Indiana Center for Vascular Biology and Medicine, Indiana University Medical Center, Indianapolis, Indiana 46202, USA.

Shock (Augusta, Ga.)
|January 31, 2004
PubMed

Insights

p38 mitogen-activated protein kinase (MAPK) inhibition attenuated endotoxin-induced heart dysfunction and cytokine production. Tumor necrosis factor alpha (TNF-alpha) plays a key role in mediating these effects, particularly for IL-1 and IL-6.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Inflammation Research

Background:

  • Cardiac myocytes produce pro-inflammatory cytokines like TNF-alpha, IL-1, and IL-6.
  • p38 MAPK is linked to oxidant-stress-induced TNF-alpha production in the heart.
  • The role of p38 MAPK in endotoxin-induced myocardial dysfunction and cytokine release remains unclear.

Purpose of the Study:

  • To investigate the contribution of p38 MAPK to endotoxin-induced myocardial contractile dysfunction.
  • To determine the role of p38 MAPK in the production of TNF-alpha, IL-1alpha, IL-1beta, and IL-6 in a bloodless endotoxin model.
  • To elucidate the relationship between TNF-alpha and other cytokine productions during endotoxin challenge.

Main Methods:

  • Isolated rat hearts were perfused using the Langendorff method.
  • Myocardial contractile function was continuously monitored during endotoxin infusion.
  • p38 MAPK activation, cytokine mRNA, and protein levels were assessed with and without p38 MAPK inhibition (SB 203580).
  • TNF-alpha sequestration was used to determine its role in mediating other cytokine production.

Main Results:

  • Endotoxin infusion progressively reduced left ventricular developed pressure and coronary flow.
  • Prior p38 MAPK inhibition significantly attenuated these declines.
  • p38 MAPK inhibition markedly decreased endotoxin-induced mRNA levels for TNF-alpha, IL-1alpha, IL-1beta, and IL-6.
  • TNF-alpha sequestration alone reduced myocardial IL-1beta and IL-6 protein levels.

Conclusions:

  • p38 MAPK activation is critical for endotoxin-induced myocardial contractile dysfunction and TNF-alpha production.
  • While p38 MAPK influences IL-1 and IL-6 production, this effect appears to be largely mediated by TNF-alpha.
  • Targeting p38 MAPK may offer a therapeutic strategy for endotoxin-induced cardiac dysfunction.

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