The loss of lung endothelial barrier function secondary to disassembly of adherens junctions and widespread endothelial cell death is a primary pathogenic feature of acute lung injury (ALI), which results in severe intractable protein-rich pulmonary edema formation. Restoration of the endothelial barrier is essential for resolving edema, yet the underlying mechanisms are poorly understood. Recent studies by us have identified endothelial regeneration as a promising future therapeutic approach. Based on our Supporting Data, we posit that fibroblast-to-endothelial cell (EC) transition is an endogenous adaptive mechanism for endothelial regeneration following lung vascular injury. We showed that inhibition of TGF? signaling promoted the recovery of endothelial barrier function. We also observed that HIF stabilization resulting from massive neutrophil extravasation during lung inflammation mediated activation of glycolysis in fibroblasts and thereby promoted fibroblast-to-EC transition. On the basis of these supporting observations, we will pursue the following Specific Aims: (1) we will delineate using lineage tracing analysis the transition of lung fibroblasts to ECs following endotoxemia; (2) we will determine the central role of TGF? signaling in regulating the transition of fibroblasts to ECs and in thereby restoring lung vascular integrity; (3) we will Identify the role of metabolic reprogramming in fibroblasts in mediating the transition to reparative ECs. We will apply multidisciplinary approaches building on the complementary and synergistic areas of expertise among the two PIs to define the signaling mechanisms that mediate fibroblast to EC transition and vascular endothelial regeneration. We hope to develop novel regenerative approaches for normalizing lung vascular integrity and fluid balance in inflammatory lung injury.
Fibroblast to endothelial cell transition is an endogenous adaptive mechanism mediating vascular endothelial regeneration. We will study the function of the TGF? signaling pathway and activation of glycolysis in mediating the transition of fibroblasts to endothelial cells and restoring lung endothelial barrier and fluid balance after inflammatory lung injury. These studies will lay the foundation for developing novel regenerative approaches for normalizing lung vascular integrity after acute lung injury.
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