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Published ahead of print on June 5, 2003, doi:10.1164/rccm.200301-041OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 4, August 2003, 436-442

A more recent version of this article appeared on August 15, 2003
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Submitted on January 13, 2003
Accepted on May 30, 2003

Integrin {alpha}4{beta}1 regulates migration across basement membranes by lung fibroblasts: A role for PTEN

Eric S White1*, Victor J Thannickal1, Shannon L Carskadon1, Emily G Dickie1, Donna L Livant2, Sonja Markwart2, Galen B Toews1, and Douglas A Arenberg1

1 Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, USA, 2 Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA

* To whom correspondence should be addressed. E-mail: docew{at}umich.edu.

Idiopathic pulmonary fibrosis is a disease 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 IPF, fibronectin signaling is both necessary and sufficient for basement membrane migration/invasion across basement membranes. This effect is mediated through the {alpha}5{beta}1 integrin, because blockade of fibronectin-{alpha}5 integrin ligation attenuated this response. In contrast, ligation of {alpha}4{beta}1 integrin inhibits basement membrane invasion by normal-lung fibroblasts but not fibrotic-lung fibroblasts. This phenotypic difference is not related to surface expression of the {alpha}4{beta}1 integrin, as demonstrated by flow cytometry. In normal-lung fibroblasts, but not in fibrotic-lung fibroblasts, we show that ligation of {alpha}4{beta}1 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 loss of {alpha}4{beta}1 signaling via PTEN confers a migratory/invasive phenotype to fibrotic-lung fibroblasts. Furthermore, this study implicates loss of PTEN function in the pathophysiology of idiopathic pulmonary fibrosis.
Key words: Pulmonary fibrosis, ECM, fibronectins, cell movement




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