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

Abstract

This study examined the hypothesis that burn trauma promotes cardiac myocyte secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and produces cardiac contractile dysfunction via the p38 mitogen-activated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into four groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats given the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postburn), 3) rats given third-degree burns over 40% total body surface area and treated with vehicle (1 ml of saline) plus lactated Ringer solution for resuscitation (4 ml x kg(-1). percent burn(-1)), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at several 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 activation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myocyte secretion of TNF-alpha. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-alpha, and prevented burn-mediated cardiac deficits. These data suggest p38 MAPK activation is one aspect of the signaling cascade that culminates in postburn secretion of TNF-alpha and contributes to postburn cardiac dysfunction.

• Authors: C Ballard-Croft, D J White, D L Maass, D P Hybki, J W Horton
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 280 Issue 5 Pg. H1970-81 (May 2001) ISSN: 0363-6135 [Print] United States
• PMID: 11299196 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Pyridines
• Tumor Necrosis Factor-alpha
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases
• SB 203580
• Calcium

Topics

• Animals
• Burns (immunology, metabolism, physiopathology)
• Calcium (pharmacokinetics)
• Coronary Circulation
• Enzyme Inhibitors (pharmacology)
• Imidazoles (pharmacology)
• In Vitro Techniques
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Muscle Fibers, Skeletal (enzymology, metabolism)
• Myocardial Contraction (drug effects, physiology)
• Myocardium (cytology, enzymology)
• Perfusion
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Survival Rate
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Resistance
• Ventricular Function, Left
• p38 Mitogen-Activated Protein Kinases