Open AccessEFFECTS OF TNF-α-CONVERTING ENZYME INHIBITION ON ACUTE LUNG INJURY INDUCED BY ENDOTOXIN IN THE RAT
Author(s) -
Mie Shimizu,
Naoki Hasegawa,
Tomoyasu Nishimura,
Yoshihiko Endo,
Yuichi Shiraishi,
Wakako Yamasawa,
Hidefumi Koh,
Sadatomo Tasaka,
Hisato Shimada,
Yukiko Nakano,
Seitaro Fujishima,
Kazuhiro Yamaguchi,
Akitoshi Ishizaka
Publication year - 2009
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/shk.0b013e3181a2adb7
Subject(s) - bronchoalveolar lavage , saline , lung , tumor necrosis factor alpha , pharmacology , chemistry , enzyme , medicine , alpha (finance) , in vitro , immunology , endocrinology , biochemistry , surgery , construct validity , patient satisfaction
We studied the effects of TNF-converting enzyme inhibition with Y-41654, which down-regulates the production of soluble TNF-alpha (sTNF-alpha), on acute lung injury induced by intratracheal administration of LPS. We first verified in vitro that pretreatment of isolated alveolar macrophages from Sprague-Dawley male rats with 20 microL of 0.1-mM Y-41654, decreased significantly (P < 0.05) the concentration of sTNF-alpha in cell supernatants induced by 10 microg/mL of LPS. We then studied four groups of rats (each n = 10) including 1) a control group, 2) an LPS group (300 microg /kg, instilled intratracheally), 3) a Y-41654 group, and 4) a treatment group treated with Y-41654 after LPS instillation. Y-41654, 10 mg/kg in 0.7 mL of phosphate-buffered saline, was administered (i.v.), 15 min before and 0.5, 1.5, 2.5, and 3.5 h after saline or LPS instillation. The animals were observed for 4 h. In the animals treated with Y-41654, the concentrations of sTNF-alpha and protein in bronchoalveolar lavage fluid, and the number of neutrophils in lung tissue and bronchoalveolar lavage fluid were significantly lower at 4 h than in the LPS group (P < 0.05). In conclusion, sTNF-alpha plays an important role in the development of acute lung injury induced by intratracheal administration of LPS, in part modulating neutrophil kinetics.