| Hypoxia and inflammatory factors/cytokines are the major cause of "shock heart" appeared after severe burn. The process of myocardial injury and cardiac dysfunction caused by either ischemia/hypoxia or inflammatory factors were complicated,and now ,there has been no effective measures in clinic to prevent its occurrence on the early stage postburn. Therefore, more clues are needed to search in order to relieve myocardial damage. Signal transduction is one of the crucial steps for cell response to many extracellular stimuti. Interrupting the key signal pathway could diminish or weaken cell effect induced by extracellular signals. But little is known about the signal pathway responsible for myocardial injury caused by hypoxia and inflammatory factors, the major extracellular stimuti to cardiac myocytes after burns.MAP kinases are an evolutionarily conserve family of enzymes that form a highly integrate network required to achieve special cell functions including cell survive and death. There major MAPK signaling pathway, ERK, JNK and p38 kinase have been identified in mammalian cells. P38 kinase and JNK are activated predominantly by stress signals, e.g. ischemia/hypoxia, cytokines and oxidative stimuti in many different cell types, which implicated in cytokine production and cell death. We postulate that severe burns activates myocardial p38 kinase or/and JNK, which subsequently play an important role in early damage of cardiomyocytes.The purpose of present study are (1) to investigate if ERK, p38 kinase and JNK in myocardium and cardiomyocyte are activated postburn; (2) to identify the role of major activated MAPK in damage of cardiomyocytes induced by hypoxia and burn sera; (3) to clarify if interventing the major activated MAPK in vivo could relieve myocardial damage on the early stage of burns.Material and Methods Both in vivo and in vitro study were cardried out in the study. 1. In in vivo study,rats inflicting with 40% TBSA of full-thickness burns were used. Activation and intracellular contribution of ERK,p38 kinase and JNK in myocardium were investigated, CK-MB activity in myocardium and plasma ,apoptosis of cardiac myocyte andleft ventricular function were measured.2. In in vitro study,cultured cardiac myocyte were injuried by hypoxia and burn sera. Activation of p38 kinase, cardiomyocyte vitality, myocyte LDH leaking and myocyte apoptosis were investigated. Under the condition of hypoxia and burn srea stimulation, iNOS, cPLA2,TNFαand IL-1βexpression ,Caspase-3 activity, MDA and membrane phospholipid content in cardiac myocyte and nitrite content in culture media were investigated before or after administration of p38 kinase inhibitor SB203580. 3. With model of 40% TBSA of full-thickess burn rats, p38 kinase activation and iNOS, cPLA2,TNFαexpression ,Caspase-3 activity in myocardium were determined .The change of CK-MB activity in myocardium,apoptosis of cardiomyocyte and left ventricular function(LVSP,LVEDP,±dp/dtmax)were investigated before or after SB203580 intervention in vivo.Result 1. Severe burn led to ERK,p38 kinase activation in myocardium and cardiomyocytes, however, JNK was not activated obviously. p38 kinase activation level in myocardium increased rapidly at 1h, peaked at 1-6h, and persisted over the 24 hrs observation period accompanying with p38 kinase nuclear translocation in cardiomyocytes.2. The CK-MB activity in myocardium dropped to its lowest at 6h, cardiomyocyte apoptosis increased to its peak at 12h, both cardiac contractile and diastole function(reflected by LVSP,LVEDP and±dp/dtmax )decreased to the lowest at 6-12h, which indicate that the myocardial damage was most serious at 6-12h postburn, the occurrence of cardiac reduction was more late than the activation of p38 kinase 3. Cardiac myocyte p38 kinase was activated rapidly by half hour, peak at 1h and 6h, and persisted to 12h by hypoxia and burn sera stimulation. Administration of SB203580 inhibited cardiac myocyte p38 kinase activation dramatically induced by hypoxia and burn ser...
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