Diffuse alveolar damage (DAD) is the histopathological hallmark of ARDS. DAD represents a continuum of injury that can lead to fibrosis. Angiogenesis is a salient feature of the fibroproliferative response, and is a mechanism that can promote fibrosis in DAD. We hypothesize that the pathogenesis of DAD with pulmonary microvascular remodeling and alveolar fibrosis is due to dysregulated angiogenesis, with over-expression of angiogenic and down-regulation of angiostatic CXC chemokines. The pro-angiogenic environment of DAD promotes fibrogenesis and impairs lung function.
The specific aims are the following: I) A) To determine whether an imbalance exists in the expression of angiogenic (ELR+), as compared to angiostatic (ELR+) CXC chemokines during the pathogenesis of DAD associated with systemic sepsis under conditions of oxidant stress. B) To establish the role that TNF-a, IL-1beta, and hyperoxia play in regulating the expression of angiogenic ELR+ CXC chemokines during the pathogenesis of DAD. C) To inhibit CXC chemokine bioactivity and determine the cause and effect relationship of specific angiogenic and angiostatic CXC chemokines in modulating the pathogenesis of DAD. II) A) To determine the molecular mechanism(s) that promote an angiogenic phenotype of human lung microvascular endothelial cells (HLMVEC) under conditions of oxidant stress. B) To establish that immunotargeting the endothelium with anti-oxidants will attenuate the development of an angiogenic phenotype. C) To ascertain that over-expression of IFN-inducible ELR+ CXC chemokine genes in HLMVEC will inhibit the development of an angiogenic phenotype. III) To demonstrate in vivo that immunotargeting the endothelium with anti-oxidant enzymes attenuates sepsis- and oxidant stress-induced DAD due to reduced angiogenesis related to inhibition of angiogenic ELR+ CXC chemokines. IV) To establish that the CXC chemokine receptor, CXCR2, is the receptor for angiogenic IL-8/ELR+ CXC chemokine mediated angiogenesis in sepsis and oxidant stress-induced DAD. V) To demonstrate in vivo that the IFN-inducible ELR+ angiostatic CXC chemokines inhibit angiogenesis and fibrogenesis associated with sepsis and oxidant stress-induced DAD. Techniques employed include: molecular, cellular, and animal models of DAD. The completion of these studies will lead to significant insight into the biology of CXC chemokines and their role in regulating angiogenesis during DAD. These findings will allow the design of therapeutic strategies that will correct imbalances in the expression of intra-alveolar CXC chemokines and attenuate the progression of alveolar fibrosis during DAD.
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