Dual immuno-regulatory effects of Y-40138 in animal models of sepsis and aspiration pneumonitis

We evaluated the dual immuno-regulatory effects of Y-40138, inhibiting tumor necrosis factor (TNF)-α production and augmenting interleukin (IL)-10 productions, in animal models of organ dysfunction related to systemic inflammatory response syndrome. Male Sprague-Dawley rats received Y-40138 (1, 10 and 30 mg/kg) or saline subcutaneously, and were subjected to cecal ligation and puncture (CLP) surgery 15 min later. Male C57Bl/6 mice received Y-40138 (30 mg/kg) or saline intravenously and were subjected to intratracheal instillation of hydrochloric acid (0.1 N, pH = 1.0) 30 min later. Survival after CLP surgery was monitored for 10 days and compared by Kaplan-Meier analysis and log rank statistics. Neutrophil count and cytokine concentrations in bronchoalveolar lavage (BAL) fluid at 12 h after intratracheal instillation were analyzed by one-way ANOVA. After CLP surgery, while 1 mg/kg of Y-40138 increased survival, 30 mg/kg of Y-40138 decreased survival (p < 0.01). After acid aspiration, Y-40138 significantly inhibited neutrophil recruitment by decreasing TNF-α / IL-10 ratio in BAL fluid (p < 0.05). Although the down regulation of pro-inflammatory cytokines and augmentation of anti-inflammatory cytokines seems a rational approach for SIRS-related multiple organ failure, further studies are needed for future clinical application of Y-40138, especially in situations compromised with microorganisms infection. Key words: Immunomodulators, sepsis, aspiration pneumonitis.