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Integrin ₄ß₁ Regulates Migration across Basement Membranes by Lung Fibroblasts

A Role for Phosphatase and Tensin Homologue Deleted on Chromosome 10

Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine; and Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Eric S. White, M.D., Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail: docew{at}umich.edu

Idiopathic pulmonary fibrosis is a disease that is characterized by fibroblast accumulation and activation in the distal airspaces of the lung. We hypothesized that fibrotic lung fibroblasts migrate/invade across basement membranes by integrin-mediated mechanisms as a means of entering alveoli. We demonstrate that in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis, fibronectin signaling is both necessary and sufficient for basement membrane migration/invasion across basement membranes. This effect is mediated through the ₅ß₁ integrin because blockade of fibronectin-₅ integrin ligation attenuated this response. In contrast, ligation of ₄ß₁ integrin inhibits basement membrane invasion by normal lung fibroblasts but not by fibrotic lung fibroblasts. This phenotypic difference is not related to surface expression of the ₄ß₁ integrin, as demonstrated by flow cytometry. In normal lung fibroblasts but not in fibrotic lung fibroblasts, we show that ligation of ₄ß₁ integrin induces a significant increase in phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity. Fibrotic lung fibroblasts express constitutively less PTEN mRNA and protein as well as phosphatase activity in comparison to normal lung fibroblasts. Together, these data suggest that a loss of ₄ß₁ signaling via PTEN confers a migratory/invasive phenotype to fibrotic lung fibroblasts. Furthermore, this study implicates a loss of PTEN function in the pathophysiology of idiopathic pulmonary fibrosis.

Key Words: pulmonary fibrosis • extracellular matrix • fibronectins • cell movement

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