ROLE OF PROTEOGLYCANS IN ELASTOLYTIC LUNG INJURY

该提案将验证蛋白酶诱导的肺损伤导致细胞表面硫酸肝素蛋白聚糖（HSPG）释放的假设，HSPG参与调节肺成纤维细胞的修复反应。提出的研究的具体目的是：1)确定HSPG在调节肺成纤维细胞对弹性损伤的反应中的作用；2)识别和表征细胞表面蛋白聚糖耗竭后弹性蛋白合成和沉积的变化；3)鉴定和表征弹性蛋白酶处理后蛋白多糖组成的变化。拟议的研究将利用药理学和酶干预的结合，产生hspg缺陷的成纤维细胞，这些成纤维细胞将受到蛋白酶治疗。形态学和生化变化将使用显微镜和生化技术来确定。描述蛋白聚糖在弹性肺损伤中的作用可能会导致对慢性阻塞性肺疾病引起的肺功能受损患者进行药物干预的新位点的确定。

DESCRIPTION This proposal will test the hypothesis that protease-induced lung injury results in the release of cell surface heparan sulfate proteoglycans (HSPG) which participate in modulating the repair responses of pulmonary fibroblasts. The specific aims of the proposed studies are 1) to define the role of HSPG in modulating the pulmonary fibroblast response to elastolytic injury; 2) to identify and characterize alterations in elastin synthesis and deposition following depletion of cell surface proteoglycans; and 3) to identify and characterize changes in proteoglycan composition following elastase treatment. The proposed studies will utilize a combination of pharmacological and enzymatic interventions which will generate HSPG-deficient fibroblasts which will be subject to protease treatment. Morphological and biochemical changes will be determined using microscopic and biochemical techniques. Delineation of the role of proteoglycans in elastolytic lung injury may lead to the identification of novel sites for drug intervention in patients with impaired pulmonary function due to chronic obstructive pulmonary disease.