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Published ahead of print on August 12, 2004, doi:10.1165/rcmb.2004-0025OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 6, December 2004, 672-678

A more recent version of this article appeared on December 1, 2004
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Submitted on January 26, 2004
Revised on August 12, 2004

Plasminogen Activator Inhibitor-1 impairs alveolar epithelial repair by binding to vitronectin

Michael H Lazar1, Paul J Christensen2, Ming Du3, Bi Yu1, Natalya M Subbotina1, Kerstin E Hanson1, Jean M Hansen1, Eric S White1, Richard H Simon1, and Thomas H Sisson1*

1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA, 2 Department of Internal Medicine, Veterans Affairs Medical Center, Ann Arbor, MI, USA; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA, 3 Department of Internal Medicine, Veterans Affairs Medical Center, Ann Arbor, MI, USA

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

The pathogenesis of pulmonary fibrosis is thought to involve alveolar epithelial injury which when successfully repaired can limit subsequent scarring. The plasminogen system participates in this process with the balance between urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) being a critical determinant of the extent of collagen accumulation that follows lung injury. Because the plasminogen system is known to influence the rate of migration of epithelial cells including keratinocytes and bronchial epithelial cells, we hypothesized that the balance of uPA and PAI-1 would affect the efficiency of alveolar epithelial cell (AEC) wound repair. Using an in vitro model of AEC wounding, we show that the efficiency of repair is adversely affected by a deficiency in uPA or by the exogenous administration of PAI-1. By using PAI-1 variants and AEC from mice transgenically deficient in vitronectin, we demonstrate that the PAI-1 effect requires its vitronectin-binding activity. Furthermore, we have found that cell motility is enhanced by the availability of vitronectin in the matrix and that the AEC-vitronectin interaction is mediated, in part, by the alpha-v beta-1 integrin. The significant effect of uPA and PAI-1 on epithelial repair suggests a mechanism by which the plasminogen system may modulate pulmonary fibrosis.




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