In patients with severe, persistent asthma, the architecture of the airway wall undergoes prominent structural changes, including increased deposition of fibronectin and collagen into the subepithelial region of the airway wall. Studies suggest that this increase in extracellular matrix deposition may play a role in the pathogenesis of asthma. However, the molecular and cellular consequences of excess matrix deposition are not known. Soluble fibronectin is polymerized into insoluble fibrils within the extracellular matrix in a cell-dependent process that is mediated by coordinate events involving the actin cytoskeleton and integrin receptors. Recent studies suggest that the interaction of cells with the extracellular matrix form of fibronectin has effects on cell cycle progression and cell migration that are distinct from those observed with soluble, protomeric fibronectin. The mechanism by which the matrix form of fibronectin gives rise to cellular phenotypes distinct from soluble fibronectin is not known. Differentiating the effect of soluble and polymerized fibronectin on cell function is essential to understanding the response of cells to the subepithelial fibrosis associated with asthma, where differences in the extent of the matrix fibronectin may significantly alter cellular phenotypes. The hypothesis to be tested in this proposal is that the interaction of cells with matrix fibronectin strengthens the linkage between the integrin and the actin cytoskeleton. This reinforcement of tension between the matrix and the cytoskeleton subsequently promotes strong adhesive contacts, inhibits cell migration, and enhances tissue contraction. In this manner, cell migration and matrix remodeling are temporally regulated by the rate and extent of fibronectin deposition into the extracellular matrix. Excess fibronectin deposition after injury would alter this relationship, triggering abnormal tissue remodeling by inhibiting cell migration and enhancing tissue contraction. The goal of these studies is to define the relationship between fibronectin polymerization, cytoskeletal organization and cell migration and to determine whether inhibition of excess fibronectin polymerization promotes normal remodeling of airways following antigen-induced airway injury. As such, the overall aim of this proposal is to identify extracellular forces that control cytoskeletal organization and cell migration in order to define therapeutic strategies aimed at controlling airway remodeling in asthma.
