Diffuse alveolar damage (DAD) of ARDS is a stereotypic response to a variety of etiologies. At post-mortem, DAD represents a continuum of overlapping phases of injury that may lead to formation of intra-alveolar granulation tissue/fibrosis. These findings are also present in ARDS patients that survive after prolonged mechanical ventilation and exposure to high FIO/2; as a significant proportion of these patients have compromised pulmonary function at one year. Angiogenesis represents a mechanism that supports intra-alveolar mesenchymal cellular proliferation and deposition of extracellular matrix in DAD. However, the specific angiogenic factors that promote angiogenesis during DAD remain to be fully elucidated. The CXC chemokines are unique are unique cytokines that can behave as either potent promoters (angiogenic factors) or inhibitors (angiostatic factors) of angiogenesis. We hypothesize that the pathogenesis of intra-alveolar angiogenesis/fibrosis associated with DAD is due to an imbalance of over-expression of angiogenic, as compared to angiostatic members of the CXC chemokine family. This paradigm of biological imbalance will favor net angiogenesis leading to intra-alveolar fibrosis and impaired lung function of ARDS patients. In the proposal, we will test this postulate by addressing the following questions: 1) Do specific cytokine networks and exposure to hyperoxia (oxidant stress) result in a preponderance of angiogenic CXC chemokines that leads to augmented intra-alveolar angiogenesis/fibrosis? 2) What is the molecular mechanism(s) for hyperoxia-induced over-expression of angiogenic CXC chemokines from human lung microvascular endothelial cells, and can gene transfer of an angiostatic CXC chemokines from human lung microvascular endothelial cells, and can gene transfer of an angiostatic CXC chemokine gene shift this imbalance and reduce the angiogenic potential of these cells? 3) Can gene transfer of an angiostatic CXC chemokine gene in vivo lead to attenuation of angiogenesis and fibrosis and an animal model of DAD? 4) Does an imbalance of over-expression of angiogenic, as compared to angiostatic CXC chemokines correlate with clinical evidence of angiogenesis/fibrosis and long-term impairment of pulmonary function in ARDS patients? Techniques employed in this application will include: a variety of molecular, immunological, cellular, bioassay, and animal models of DAD. The elucidation of the pathobiology of the imbalance of angiogenic, as compared to angiostatic CXC chemokines will permit the development of novel and targeted therapy aimed specifically at attenuation intra-alveolar angiogenesis/fibrosis, leading to improved preservation of lung function in ARDS.
Showing the most recent 10 out of 88 publications
