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(American Journal of Pathology. 2006;169:1624-1632.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051053

Dual Role for Plasminogen Activator Inhibitor Type 1 as Soluble and as Matricellular Regulator of Epithelial Alveolar Cell Wound Healing

François Maquerlot*, Stephane Galiacy{dagger}, Michel Malo*, Christophe Guignabert{ddagger}, Daniel A. Lawrence§, Maria-Pia d’Ortho{ddagger} and Georgia Barlovatz-Meimon*

From Informatique, Biologie Intégrative et Systèmes Complexes,* FRE 2873 Centre National de la Recherche Scientifique, Université d’Evry, Génopole, Evry, and Université Paris 12, Créteil, France; the Département de Physiologie,{ddagger} INSERM U651, Hôpital H. Mondor, Créteil, France; the Cell Biology Department,{dagger} Duke University, Durham, North Carolina; and the Department of Internal Medicine,§ University of Michigan School of Medicine, Ann Arbor, Michigan

Epithelium repair, crucial for restoration of alveolo-capillary barrier integrity, is orchestrated by various cytokines and growth factors. Among them keratinocyte growth factor plays a pivotal role in both cell proliferation and migration. The urokinase plasminogen activator (uPA) system also influences cell migration through proteolysis during epithelial repair. In addition, the complex formed by uPAR-uPA and matrix-bound plasminogen activator inhibitor type-1 (PAI-1) exerts nonproteolytic roles in various cell types. Here we present new evidence about the dual role of PAI-1 under keratinocyte growth factor stimulation using an in vitro repair model of rat alveolar epithelial cells. Besides proteolytic involvement of the uPA system, the availability of matrix-bound-PAI-1 is also required for an efficient healing. An unexpected decrease of healing was shown when PAI-1 activity was blocked. However, the proteolytic action of uPA and plasmin were still required. Moreover, immediately after wounding, PAI-1 was dramatically increased in the newly deposited matrix at the leading edge of wounds. We thus propose a dual role for PAI-1 in epithelial cell wound healing, both as a soluble inhibitor of proteolysis and also as a matrix-bound regulator of cell migration. Matrix-bound PAI-1 could thus be considered as a new member of the matricellular protein family.




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