Dual role for plasminogen activator inhibitor type 1 as soluble and as matricellular regulator of epithelial alveolar cell wound healing.
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.
Maquerlot
François
F
Informatique, Biologie Intégrative et Systèmes Complexes, FRE 2873 Centre National de la Recherche Scientifique, Université d'Evry, Génopole, Evry, France.
Galiacy
Stephane
S
Malo
Michel
M
Guignabert
Christophe
C
Lawrence
Daniel A
DA
d'Ortho
Maria-Pia
MP
Barlovatz-Meimon
Georgia
G
D000818:Animals; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005341:Fibrinolysin / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D051523:Fibroblast Growth Factor 7; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator