1. Effect of doxycycline on sulfur mustard-induced respiratory lesions in guinea pigs.: Doxycycline Prevents SM-Induced Respiratory Lesions
- Author
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Marie-Pia d'Ortho, Stéphane Galiacy, Laurent Taysse, Séraphin Delamanche, Emmanuelle Planus, Jean-Henri Calvet, Christophe Guignabert, Physiopathologie et Thérapeutiques Respiratoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10, Centre d'Etudes du Bouchet, Délégation Générale pour l'Armement, Service de physiologie, explorations fonctionnelles [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and This work was funded by the DGA and the Institut National de la Sante et de la Recherche Medicale (France).
- Subjects
Male ,MESH: Inflammation ,Gelatinases ,Physiology ,MESH: Chemical Warfare Agents ,Respiratory System ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Matrix metalloproteinase ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,chemistry.chemical_compound ,0302 clinical medicine ,vesicant agents ,Gelatinase ,MESH: Animals ,MESH: Gelatinases ,Chemical Warfare Agents ,MESH: Doxycycline ,MESH: Respiratory System ,Doxycycline ,0303 health sciences ,MESH: Protease Inhibitors ,Sulfur mustard ,Anti-Bacterial Agents ,3. Good health ,medicine.anatomical_structure ,MESH: Epithelial Cells ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,030220 oncology & carcinogenesis ,medicine.drug ,Pulmonary and Respiratory Medicine ,Guinea Pigs ,protease inhibitors ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,MESH: Guinea Pigs ,Microbiology ,Guinea pig ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,MESH: Anti-Bacterial Agents ,Physiology (medical) ,Mustard Gas ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,medicine ,Animals ,Zymography ,030304 developmental biology ,Inflammation ,Tissue Inhibitor of Metalloproteinase-2 ,Tissue Inhibitor of Metalloproteinase-1 ,doxycycline ,blistering agents ,Epithelial Cells ,Cell Biology ,Molecular biology ,MESH: Male ,MESH: Mustard Gas ,MESH: Tissue Inhibitor of Metalloproteinase-2 ,MESH: Tissue Inhibitor of Metalloproteinase-1 ,chemistry ,proteases ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Respiratory tract - Abstract
9 pages; International audience; 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.
- Published
- 2005