Control of pulmonary elastolytic injury by proteoglycans

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

An imbalance in protease/anti-protease activity is believed to underlie the development of obstructive pulmonary diseases such as emphysema. While elastin degradation is pivotal to this process it is clear that there are other targets of the excessive proteolysis that are involved in regulating the structural integrity of the alveolar wall. Our studies have demonstrated that pulmonary proteoglycans are a major target for elastase degradation. We have demonstrated that heparan sulfate proteoglycans in the extracellular matrix of pulmonary fibroblast are sites of storage for FGF2, a potent down regulator of elastin gene transcription. Within this project we aim to identify the functions and underlying mechanisms of proteoglycans as modulators of elastolytic injury in the lung. Our hypothesis is that elastase-induced lung injury results in the release of proteoglycans, growth factors and cytokines which mediate subsequent matrix repair. In the present project we will focus on the function of released proteoglycans as mediators of growth factor and elastase activity, the synthesis of proteoglycans after injury regulated by cytokines, and the relationship between proteoglycans and elastogenesis. The specific aims of this project are to: 1) Identify the role of elastase released heparan sulfate proteoglycans in modulating elastase activity, FGF2 receptor activation, and the synthesis of proteoglycans and elastin, 2) Define the role of the small chondroitan sulfate proteoglycan, decorin, in modulating the elastase-induced cellular response, 3) Determine the consequences of elastase digestion on FGF2 nuclear localization and on FGF2 and TGFbeta transport through extracellular matrix, and 4) Examine the effects of elastolytic injury on proteoglycan and growth factor levels in normal mice and mice deficient in IL-1beta and TNFalpha receptors, and decorin. These studies will help identify aspects of the lung response to injury that are mediated by proteoglycans. Ultimately, these studies could provide critical insight into the development of new treatments for obstructive pulmonary diseases targeting the regulatory role of proteoglycans.