Effect of doxycycline on sulfur mustard-induced respiratory lesions in guinea pigs.
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.
Guignabert
Christophe
C
Unité U492 de l'Institut National de la Santé et de la Recherche Médicale and Départment de Physiologie, Faculté de Médecine, Université Paris, Créteil, France.
Taysse
Laurent
L
Calvet
Jean-Henri
JH
Planus
Emmanuelle
E
Delamanche
Séraphin
S
Galiacy
Stéphane
S
d'Ortho
Marie-Pia
MP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004318:Doxycycline / Q000008:administration & dosage*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D018093:Gelatinases / Q000378:metabolism; D006168:Guinea Pigs; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008297:Male; D009151:Mustard Gas / Q000633:toxicity*; D011480:Protease Inhibitors / Q000008:administration & dosage*; D012137:Respiratory System / Q000201:enzymology* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D000900:Anti-Bacterial Agents; D002619:Chemical Warfare Agents; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D004318:Doxycycline; D009151:Mustard Gas