Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory disease affecting the pulmonary, cardiovascular, and musculoskeletal systems. Cigarette smoke is the most common cause of COPD. Extracellular matrix remodeling in response to smoke-induced tissue injury is thought to contribute to the pathogenesis of COPD. Changes in the deposition and physiologic properties of individual extracellular matrix proteins in response to cigarette smoke have yet to be determined. The goal of this proposal is to establish factors that regulate the deposition, conformation, and physiologic properties of extracellular matrix fibronectin and investigate if these factors are localized to the lung tissue in response to cigarette smoke. Fibronectin and vitronectin are extracellular matrix glycoproteins upregulated in tissue injury. Matrix fibronectin mediates processes necessary for tissue repair, including cell growth, migration, and contractility as well as the composition and mechanical properties of the extracellular matrix. Regulators of these fibronectin-mediated cellular responses are unknown. Emerging data suggest that a conformation dependent heparin binding domain in the 111-1 region of fibronectin contributes to its physiologic activities. My data indicate that adhesion of cells to vitronectin alters the conformation and cell growth response of matrix fibronectin. I hypothesize that vitronectin serves to regulate the deposition, physiologic properties, and conformation of the 111-1 heparin binding domain of extracellular matrix fibronectin during tissue injury. Fibronectin is present in the lavage fluid of smokers and localized to the bronchioles of smoke-exposed mice. Our data show that vitronectin is also present in the lavage fluid of smoke-exposed mice, suggesting that vitronectin is deposited into lung tissue in response to cigarette smoke. These data suggest that both vitronectin and fibronectin contribute to smoke-induced extracellular matrix remodeling.
The aims of this proposal are: (1) Quantify smoke-induced changes in the deposition of vitronetin and fibronectin in the pulmonary tissue over time and identify smoke-induced conformational changes in the 111-1 domain of fibronectin;(2) Determine conformational and physiologic differences in extracellular matrix fibronectin formed by collagen- and vitronectin-adherent cells;and (3) Characterize the role of the 111-1 heparin binding domain in fibronectin-mediated cellular responses. Relevance: COPD is the fourth leading cause of death in the U.S. Despite this, there are no drug therapies that stop the progression of COPD. The goal of this proposal is to gain an understanding of factors that contribute to development of COPD in hopes of identifing new targets for drug therapy.
|Gildner, Candace D; Roy, Daniel C; Farrar, Christopher S et al. (2014) Opposing effects of collagen I and vitronectin on fibronectin fibril structure and function. Matrix Biol 34:33-45|