Burn injury initiates a series of pathophysiological changes. A progressive fall in left ventricular (LV) contractile function despite aggressive fluid resuscitation has been reported in both clinical and experimental studies of burn injury. However, the source(s) or the signaling pathways involved in burn-induced myocardial dysfunction remain largely unknown. Recent studies from our group indicated that gut-derived myocardial depressant factors carried in intestinal lymph trigger myocardial contractile depression. In addition, our preliminary studies demonstrated that the physiologically relevant concentrations of mesenteric lymph collected from rats receiving 40 % burn injury (burn lymph), but not lymph from sham-burned rats (control lymph), to ventricular myocytes isolated from healthy rats leads to a significant alterations in action potential duration associated with disturbed Ca2+homeostasis. In other preliminary work, we have found that burn lymph increases myocyte size, mitogen-activated protein kinases and cell death of cultured neonatal rat ventricular myocytes after 24 hrs incubation, suggesting a common mechanistic link between burn trauma and hypertrophic heart disease. In this proposal, we will capitalize on these discoveries and propose to further investigate the cellular and molecular mechanisms involved in burn-induced myocardial dysfunction and the roles of burn lymph in physiological and pathophysiological conditions. To begin understanding the cellular basis for altered myocardial function, this proposal focuses on cellular mechanisms important for myocardial Ca2+ homeostasis. We hypothesize that 1) burn injury-induced LV dysfunction is secondary to gut-derived factor(s) contained in mesenteric lymph (burn lymph), and 2) changes in ionic currents and Ca2+-cycling proteins caused by burn lymph are involved in burn-induced LV dysfunction and ultimately to heart failure (HF). To test the hypothesis, this grant proposal also includes genomics and protein chemistry to elucidate valuable information in the heart after burn injury. This research is fundamental to our understanding of molecular mechanisms of burn-related myocardial dysfunction. A better understanding of molecular etiology and downstream mechanisms could lead to improved therapeutic measures to reduce the morbidity and mortality associated with burn injury.
