Dual role for plasminogen activator inhibitor type 1 as soluble and as matricellular regulator of epithelial alveolar cell wound healing

Am J Pathol. 2006 Nov;169(5):1624-32. doi: 10.2353/ajpath.2006.051053.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism*
  • Fibrinolysin / pharmacology
  • Fibroblast Growth Factor 7 / pharmacology
  • Male
  • Models, Biological
  • Plasminogen Activator Inhibitor 1 / immunology
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Protein Transport / drug effects
  • Pulmonary Alveoli / cytology*
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Solubility / drug effects
  • Urokinase-Type Plasminogen Activator / metabolism
  • Wound Healing / drug effects
  • Wound Healing / physiology*


  • Plasminogen Activator Inhibitor 1
  • Fibroblast Growth Factor 7
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator