Grant: Operating Grant

Morbidity and mortality of severely burned patients still remain unacceptably high. Recent evidence indicates that hypermetabolism, a hallmark of severely burned patients, is a major contributor to these detrimental outcomes. The upstream mediators inducing these changes were long thought to be cortisol, catecholamines, and glucagon. However, neither blockade of cortisol nor attenuation of glucagon alleviated post-burn hypermetabolic inflammatory responses. Also, several unexpected cellular processes have come into the spotlight in the glucose and lipid metabolism research recently as potential mediators of metabolic dysfunction in various settings, namely: endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and activation of the NLRP3 inflammasome. We therefore hypothesize that catecholamines, which are 10-40 fold increased post-burn, are the central mediators inducing post-burn hypermetabolism, associated with cellular stress responses of ER stress, mitochondrial dysfunction, and activation of the inflammasome, resulting in poor clinical outcomes. To test this hypothesis, we suggest blocking catecholamine effects by administration of a non-selective beta 1/2-receptor antagonist, Propranolol. We chose Propranolol, not only because of its long-demonstrated clinical efficacy and safety, but also as it has been shown to affect post-burn lipolysis. We expect that catecholamine blockade via Propranolol will attenuate the intracellular stress signaling cascades of ER stress and inflammasome activation, normalizing burn-induced alterations in glucose and lipid metabolism, leading to decreased hypermetabolic responses, which will improve post-burn morbidity and mortality. The relevance of this project is that we will not only determine fundamental mechanisms leading to hypermetabolism in severely burned patients but that we will use a clinically effective perturbation that is readily available and safe in burn patients with the hope of improving their outcomes.