HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/L67    most recent 00475.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Guignabert, C. Articles by d'Ortho, M.-P. Search for Related Content PubMed PubMed Citation Articles by Guignabert, C. Articles by d'Ortho, M.-P.

Effect of doxycycline on sulfur mustard-induced respiratory lesions in guinea pigs

¹Unité U492 de l'Institut National de la Santé et de la Recherche Médicale and Département de Physiologie, Faculté de Médecine, Université Paris XII, 94010 Créteil; ²Centre d'Etudes du Bouchet (Centre de Recherche Médicale de la Défense), 91710 Vert Le Petit; and ³Service de Physiologie-Explorations Fonctionnelles, Hôpital Henri Mondor Assistance Publique-Hôpitaux de Paris, 94010 Créteil, France

Submitted 22 December 2004 ; accepted in final form 1 March 2005

Respiratory tract lesions induced by the chemical warfare agent sulfur mustard (SM) are characterized by epithelial damages associated with inflammatory cell infiltration. Here we evaluated the imbalance between gelatinase and tissue inhibitors of metalloproteinases (TIMPs), and we tested pretreatment with the protease inhibitor doxycycline. Guinea pigs were intoxicated intratracheally with SM and evaluated 24 h after exposure. Matrix metalloproteinase (MMP) gelatinase activity of bronchial lavage (BL) fluid from SM-exposed guinea pigs was high compared with controls, as shown by both zymography and biotinylated substrate degradation, whereas TIMP-1 and -2 levels by immunoblotting were similar. Extensive areas of lysis were evidenced by in situ zymography, indicating imbalance between gelatinases and inhibitors towards net proteolytic activity. Doxycycline pretreatment resulted in 1) decreased gelatinase activity (zymography, free gelatinase activity assay, and in situ zymography); 2) decreased inflammation (BL fluid cellularity and protein level); and 3) dramatic decrease in histological epithelial lesions. Our results suggest inadequate levels of TIMP to counteract increased gelatinase activity and further support a role for MMP gelatinases in SM-induced respiratory lesions. They also suggest that doxycycline may hold promise as a therapeutic tool.

vesicant agents; blistering agents; proteases; doxycycline; protease inhibitors