JTE-607, a cytokine release blocker, attenuates acid aspiration-induced lung injury in rats

Abstract

The present study was designed to clarify the effects of (-)-ethyl N-{3,5-dichloro-2-hydroxy-4-[2-(4-methyl-piperazin-1-yl)ethoxy]benzoyl}- l-phenylalaninate dihydrochloride (JTE-607), a novel multiple cytokine inhibitor, on hydrochloric acid (HCl) aspiration lung injury in rats. HCl (0.1 N, 2 ml kg −1) was instilled into male Sprague–Dawley rats that were pretreated with or without JTE-607 (30 or 75 mg kg −1 h −1). As a control, normal saline (2 ml kg −1) was instilled in rats. All the animals were anesthetized with intraperitoneally injected pentobarbital sodium (40 mg kg −1). Bronchoalveolar lavage was performed 5 h (h) after HCl or normal saline instillation. In bronchoalveolar lavage fluid, the increases in total nuclear cell counts, neutrophil counts, optical density at 412 nm as an indication of pulmonary hemorrhage, concentrations of albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant induced by HCl instillation were significantly reduced by JTE-607 pretreatment. The level of expression of tumor necrosis factor-α and interleukin-6 mRNA in lung tissue was analyzed. The mean expression level of tumor necrosis factor-α and interleukin-6 mRNA in the JTE-607 group was lower than that in the HCl and NS groups. The wet-to-dry weight ratio was also determined, and JTE-607 at the dose of 75 mg kg −1 h −1 significantly attenuated the increased wet-to-dry weight ratio induced by HCl. These results suggest that JTE-607 can inhibit the production of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6 and cytokine-induced neutrophil chemoattractant and attenuate acid-induced lung injury in rats. This agent might be therapeutically useful for lung injury.