ROLE OF PROTEOGLYCANS IN ELASTOLYTIC LUNG INJURY

描述本提案将检验蛋白酶诱导的肺损伤导致细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）释放的假设，HSPG参与调节肺成纤维细胞的修复反应。拟定研究的具体目的是：1）确定HSPG在调节肺成纤维细胞对弹性蛋白溶解性损伤的反应中的作用; 2）鉴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）鉴别和表征弹性蛋白酶处理后蛋白聚糖组成的变化。拟定的研究将利用药理学和酶干预的组合，其将产生HSPG缺陷的成纤维细胞，其将经受蛋白酶处理。将使用显微镜和生物化学技术确定形态学和生物化学变化。蛋白多糖在弹性蛋白溶解性肺损伤中的作用的描述可能会导致对慢性阻塞性肺疾病所致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.