Vitronectin regulates lung tissue remodeling and emphysema in chronic obstructive pulmonary disease.

Abstract

Vitronectin (VTN) is an important extracellular matrix protein in tissue remodeling, but its role in COPD is unknown. We show that VTN regulates tissue remodeling through urokinase plasminogen activator (uPA) signaling pathway in COPD. In human COPD airways and bronchoepithelial cells and the airways of mice with cigarette smoke (CS)-induced experimental COPD, VTN protein was not changed, but downstream uPA signaling was altered (increased plasminogen activator inhibitor-1, uPAR) that induced collagen and airway remodeling. In the parenchyma, VTN levels were decreased, uPA signalling pathway differentially altered and collagen reduced in lung fibroblasts from human and lung parenchyma in experimental COPD. Vtn inhibition with siRNA in mouse fibroblasts altered uPA signalling increased matrix metalloproteinase-12, and reduced collagen, whereas over-expression restored collagen production after CS extract challenge. Vtn^-/- and Vtn siRNA-treated mice had exaggerated inflammation, emphysema and impaired lung function compared to controls with CS-induced COPD. Restoration of VTN in the parenchyma may be a therapeutic option for emphysema and COPD.