title: Activation of stress-responsive pathways by the sympathetic nervous system in burn trauma.
abstract: We have shown previously that bum trauma activates the stress responsive proteins, p38 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK), and NF-kappaB, and we have shown further that p38 MAPK is an important mediator of cardiomyocyte TNF-alpha secretion and cardiac dysfunction in burn trauma. Since burn trauma causes a rise in circulating catecholamine levels, we hypothesized that this increased sympathetic activity may function as an upstream activator of the p38 MARK pathway in burn trauma. This study determined whether the alpha1-adrenergic receptor ligand phenylephrine could mimic burn trauma activation of p38 MAPK, JNK, and NF-kappaB nuclear translocation; and the effect of the alpha1-adrenergic receptor antagonist prazosin on either phenylephrine or burn-mediated activation of the stress response pathway was examined. Sprague Dawley rats were divided into seven groups: Group 1, controls; Group 2, phenylephrine-treated (2 microg/kg, i.v.) control rats; Group 3, phenylephrine-treated plus prazosin-treated (1 mg/kg, i.v.) control rats; additional rats were given burn over 40% total body surface area (TBSA) and received vehicle (1 mL of 2% sucrose, p.o.) plus fluid resuscitation (Group 4), while in Group 5, burn rats were given prazosin (1 mg/kg, p.o.) plus fluid resuscitation. In Groups 6 and 7, sham-burned rats were given either vehicle (1 mL of 2% sucrose, p.o.) or prazosin (1 mg/kg, p.o.) to provide appropriate controls. Administration of phenylephrine to rats caused a significant activation of cardiac p38 MAPK/JNK activities (Western blot) and cardiac NF-kappaB nuclear translocation (electrophoretic mobility shift assay, EMSA). Prazosin blocked phenylephrine mediated changes in p38 MAPK/JNK activities. Burn trauma activated cardiac p38 MAPK/JNK and NF-kappaB, increased TNF-alpha secretion by cardiomyocytes, and impaired cardiac function. Prazosin treatment in burns interrupted the burn-mediated signaling cascade, decreasing TNF-alpha secretion by cardiomyocytes and preventing post-burn cardiac contractile dysfunction. Thus, burn trauma-related sympathetic activity likely activates the stress-responsive cascade, which regulates myocardial TNF-alpha transcription/translation and culminates in cardiac contraction and relaxation defects.
authors.affiliation: University of Texas Southwestern Medical Center, Department of Surgery, Dallas 75390-9160, USA.
authors.forename: Cherry
authors.initials: C
authors.lastname: Ballard-Croft
authors.forename: David L
authors.initials: DL
authors.lastname: Maass
authors.forename: Patricia
authors.initials: P
authors.lastname: Sikes
authors.forename: Jean
authors.initials: J
authors.lastname: White
authors.forename: Jureta
authors.initials: J
authors.lastname: Horton
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002056:Burns / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D004789:Enzyme Activation; D006339:Heart Rate; D006439:Hemodynamics; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013312:Stress, Physiological; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000317:Adrenergic alpha-Antagonists; D016328:NF-kappa B; D018340:Receptors, Adrenergic, alpha-1; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011224:Prazosin