Prophylactic effect of JTE-607 on LPS-induced acute lung injury in rats with CINC-1 inhibition.
OBJECTIVE
JTE-607, a multiple cytokine inhibitor, was evaluated in lipopolysaccharide (LPS)-induced acute lung injury in rats in vivo and in vitro.


METHODS
LPS instillation into airways of rats was performed. JTE-607 at 3-30 mg/kg and dexamethasone at 3 mg/kg were administered intravenously at 10 min and 0 min for JTE-607, and 60 min for dexamethasone prior to the LPS instillation (n = 8). Cytokine-induced neutrophil chemoattractant (CINC)-1 level and myeloperoxidase (MPO) activity in lung were measured at 4 h after LPS instillation, and at 24 h for lung wet weight measurement and histological study. LPS-induced CINC-1 production by rat alveolar macrophages were also measured in vitro.


RESULTS
JTE-607 and dexamethasone showed a significant reduction of increased CINC-1 level and MPO activity in lung after LPS treatment in vivo. Increased wet weight was also significantly inhibited. Histological studies revealed that JTE-607 and dexamethasone significantly inhibited LPS-induced accumulation of peribronchial neutrophils and eosinophils, and perivascular edema. JTE-607 and dexamethasone suppressed CfNC-1 synthesis by rat alveolar macrophages in vitro with IC50 values of 12.4 microM and 2.3 nM, respectively.


CONCLUSIONS
These results indicate that JTE-607 has an inhibitory effect on LPS-induced rat lung inflammation in parallel with CINC-1 reduction. The effect of JTE-607 was suggested to be through direct inhibition of CINC-1 production from rat alveolar macrophages. JTE-607 may thus be efficacious in cytokine-mediated lung inflammation such as acute respiratory distress syndrome.
Iwamura
H
H
Japan Tobacco Inc., Central Pharmaceutical Research Institute, Takatsuki, Osaka. hiroyuki.iwamura@ims.jti.co.jp
Inushima
K
K
Takeuchi
K
K
Kakutani
M
M
Wakitani
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D054360:Chemokine CXCL1; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000517:prevention & control*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; C468268:JTE 607; D008070:Lipopolysaccharides; D010879:Piperazines; D010649:Phenylalanine; D003907:Dexamethasone