The time course of cardiac NF-kappaB activation and TNF-alpha secretion by cardiac myocytes after burn injury: contribution to burn-related cardiac contractile dysfunction.
Previous studies have suggested that cardiac synthesis of TNF-alpha contributes to myocardial dysfunction in several models of trauma, sepsis and ischemia. Therefore, it is likely that myocyte secretion of TNF-alpha occurs early after major burn trauma, contributing to progressive cardiac contractile dysfunction that is characteristic of thermal injury. This study examined the time course of nuclear translocation of the transcription factor NF-kappaB, the time course of TNF-alpha secretion by cardiomyocytes after burn trauma, and the development of cardiac contractile defects. Rats were given burn injury over 40% TBSA (sham burns included for controls), and fluid resuscitation included lactated Ringer's solution, 4 mL/kg/%burn. Subsets of rats were sacrificed at several times postburn (1, 2, 4, 8, 12, 18 and 24 h), hearts were harvested to prepare cardiomyocytes (N = 4 rats/group/time period), to prepare nuclear fractions to measure burn-induced NF-kappaB activation (N = 3-4 rats/group/time period), or to examine the time course of postburn cardiac contractile dysfunction (N = 6-7 rats/group/time period). Despite aggressive fluid resuscitation, burn trauma activated NF-kappaB 4 h postburn, and this activation persisted over the 24 h study period. In addition, burn trauma produced a time-related increase in TNF-alpha secretion by cardiac myocytes with cytokine secretion evident 1 h postburn. Cardiac dysfunction occurred 8 h postburn and persisted over the 24 h study period. Administration of a strategy designed to inhibit NF-kappaB activation (N-acetyl-leucinyl-leucinyl-norleucinal, ALLN, 50 mg/kg, in additional groups of burn rats) inhibited TNF-alpha secretion by cardiac myocytes and improved myocardial function. This study confirms that burn trauma activates myocardial NF-kappaB and promotes cardiomyocyte secretion of TNF-alpha. This inflammatory cascade preceded the appearance of cardiac dysfunction, suggesting that cardiac myocyte derived TNF-alpha contributes, in part, to postburn cardiac contractile deficits.
Maass
David L
DL
The University of Texas Southwestern Medical Center at Dallas, Department of Surgery, 75390-9160, USA.
Hybki
Dixie Peters
DP
White
Jean
J
Horton
Jureta W
JW
D000818:Animals; D002056:Burns / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology; D006439:Hemodynamics; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007700:Kinetics; D007976:Leupeptins / Q000494:pharmacology; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D018836:Inflammation Mediators; D007976:Leupeptins; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C063261:acetylleucyl-leucyl-norleucinal