Mechanisms of age-related inflammatory response in hemorrhagic shock

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DESCRIPTION (provided by applicant): The clinical scenario of trauma and severe hemorrhage is characterized by an overwhelming activation of several inflammatory mediators and by modification of the interactions between leukocytes and endothelial cells, leading to sequestration of neutrophils into the tissues and organs. Clinical observations suggest that pediatric trauma victims have lower incidence of multiple organ dysfunction syndrome (MODS) than adult patients. However, the precise molecular mechanisms are not clear. In preliminary in vivo studies we have found that under physiological conditions, lung expression of the peroxisome proliferator activated receptor-y PARY), a nuclear receptor with putative anti-inflammatory role, is a function of the aging process and is maximally expressed at young age, while it declines in mature rats. This age-dependent decline of PPARy expression inversely correlates with phosporylation of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinases known to be capable of modifying PPARy activity. We also have found that mature rats, when subjected to hemorrhagic shock, exhibit a more pronounced lung and liver injury when compared with young rats. Our hypothesis is that the severity of the systemic inflammatory response during hemorrhagic shock is age-dependent and is modulated at the nuclear level by a diverse regulation of the PPARy pathway. Three interrelated specific aims will test this hypothesis. (1) We will define the age-dependency of the PPARy pathway during the aging process under normal physiological conditions and after hemorrhagic shock in vivo. (2) With "gain-of-function" and "loss-of-function" studies, we will evaluate the precise role of the PPARy pathway on the systemic inflammatory response during hemorrhagic shock in vivo in young and mature rats. (3) We will identify the molecular mechanisms of the age-dependent dysregulation of PPARy by evaluating the role of the upstream regulatory kinases ERK1/2. A common clinical observation in intensive care units is that pediatric patients are less susceptible to develop multiple organ dysfunction syndrome and recover relatively uneventfully than adult trauma victims. Our project is aimed to identify the molecular mechanisms responsible of the diverse inflammatory response in the adult and the pediatric patients, and will provide valuable information for the developing of novel therapeutic approaches for the treatment of trauma and hemorrhage.