Development of cell-based treatment of Acute Lung Injury (ALI) poses multiple therapeutic challenges and pitfalls. The main features of ALI are impairment of oxygenation secondary to leaky lung microvessels and protein-rich edema. Injury of the endothelial cell (EC) barrier in pulmonary microvessels and resulting increased microvascular permeability to protein is the primary factor responsible for the pulmonary edema. Bone marrow (BM) -derived endothelial progenitor cells (EPCs) may afford an opportunity to prevent and/or reverse lung vascular injury and edemagenesis. However, the potential value of EPC treatment has not been systematically addressed and the mechanistic basis of EPC-mediated repair of the breeched endothelial barrier remains unclear. Our Supporting Data suggest the usefulness of EPC engraftment or EPC paracrine action in preventing sepsis induced-lung vascular injury and inflammation. However, little is known about the mechanisms of reconstitution of barrier function induced by EPCs. We will test the hypothesis that EPC engraftment and/or EPC paracrine effect prevents restores normal lung microvascular and resolves lung edema and inflammation by determining the (1) physiological outcomes of EPCs in sepsis-induced models of lung microvascular injury and edema formation and whether EPCs resolve lung edema and inflammation and promote survival;(2)the role of FoxM1 transcription factor in mediating ECproliferation and endothelial barrier regeneration induced by EPCs;(3) roles (a) of the sequential activation of EC RhoGTPase, RhoA, Rac1 and Cdc42, induced by EPCs and (b) of integrin alphasbetai expressed in EPCs in promoting EPC engraftment following lung microvascular injury; (4) role of lung inflammation versus resolved inflammation in the re-constitution of the barrier by EPCs;and (5) efficacy and safety of EPCtreatment in large animal model of sepsis-induced lung microvascular injury and ALI. These studies will determine the mechanisms of improved survival and address the relevancy of a cell-based approach in ALI. It is hoped that the outcome of these studies will provide new information directly relevant to the therapeutic value of EPCs for the treatment in ALI.
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