Effects of TNF-alpha-converting enzyme inhibition on acute lung injury induced by endotoxin in the rat.
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.
Shimizu
Mie
M
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Hasegawa
Naoki
N
Nishimura
Tomoyasu
T
Endo
Yoshihiko
Y
Shiraishi
Yoshiki
Y
Yamasawa
Wakako
W
Koh
Hidefumi
H
Tasaka
Sadatomo
S
Shimada
Hisato
H
Nakano
Yasushi
Y
Fujishima
Seitaro
S
Yamaguchi
Kazuhiro
K
Ishizaka
Akitoshi
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D055371:Acute Lung Injury / Q000209:etiology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013386:Succinates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; C547133:Y 41654; D051722:ADAM Proteins; D000072198:ADAM17 Protein