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Transforming growth factor-1 increases airway wound repair via MMP-2 upregulation: a new pathway for epithelial wound repair?

¹Institut National de la Santé et de la Recherche Médicale, Unité U651, Faculté de Médecine, Université Paris XII, Créteil; ²Service d'Anatomie Pathologique, Centre Hospitalier Universitaire de Caen, Caen; ³Service d'ORL et de Chirurgie Cervico-Faciale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris et Hôpital Intercommunal, Créteil; ⁴Service de Physiologie-Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil; and ⁵Département de génétique, cytogénétique et embryologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France

Submitted 4 April 2005 ; accepted in final form 6 January 2006

In vivo, transforming growth factor (TGF)-1 and matrix metalloproteinases (MMPs) present at the site of airway injury are thought to contribute to epithelial wound repair. As TGF-1 can modulate MMP expression and MMPs play an important role in wound repair, we hypothesized that TGF-1 may enhance airway epithelial repair via MMPs secreted by epithelial cells. We evaluated the in vitro influence of TGF-1 on wound repair in human airway epithelial cells cultured under conditions allowing differentiation. The results showed that TGF-1 accelerated in vitro airway wound repair, whereas MMP inhibitors prevented this acceleration. In parallel, we examined the effect of TGF-1 on the expression of MMP-2 and MMP-9. TGF-1 induced a dramatic increase of MMP-2 expression with an increased steady-state level of MMP-2 mRNA, contrasting with a slight increase in MMP-9 expression. To confirm the role of MMP-2, we subsequently evaluated the effect of MMP-2 on in vitro airway wound repair and demonstrated that the addition of MMP-2 reproduced the acceleration of wound repair induced by TGF-1. These results strongly suggest that TGF-1 increases in vitro airway wound repair via MMP-2 upregulation. It also raises the issue of a different in vivo biological role of MMP-2 and MMP-9 depending on the cytokine microenvironment.

human nasal epithelial cells; matrix metalloproteinase-9; wound healing; cell migration

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