ROLE OF PROTEOGLYCANS IN ELASTOLYTIC LUNG INJURY

本提案将验证一种假说，即蛋白酶诱导的肺损伤会导致细胞表面硫酸乙酰肝素蛋白多糖(HSPG)的释放，而HSPG参与调节肺成纤维细胞的修复反应。这些研究的具体目的是：1)明确HSPG在调节肺成纤维细胞对弹性损伤反应中的作用；2)鉴定和表征细胞表面蛋白多糖耗尽后弹性蛋白合成和沉积的变化；3)鉴定和表征弹性酶处理后蛋白多糖组成的变化。拟议的研究将利用药物和酶干预的组合，产生HSPG缺陷的成纤维细胞，这些成纤维细胞将接受蛋白酶治疗。形态和生化变化将使用显微镜和生化技术来确定。阐明蛋白多糖在弹性溶解性肺损伤中的作用可能有助于确定药物干预慢性阻塞性肺疾病所致肺功能受损患者的新部位。

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.