African Journal of
Pharmacy and Pharmacology

  • Abbreviation: Afr. J. Pharm. Pharmacol.
  • Language: English
  • ISSN: 1996-0816
  • DOI: 10.5897/AJPP
  • Start Year: 2007
  • Published Articles: 2298

Full Length Research Paper

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

Hiroyuki Seki1, Koichi Suda2, Kiyoshi Moriyama3*, Yoshiki Shiraishi4,5, Koichi Fukunaga4, Sadatomo Tasaka4, Yuko Kitagawa2, Akitoshi Ishizaka4 and Junzo Takeda1
1Department of Anesthesiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. 2Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. 3Department of Anesthesiology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. 4Division of Pulmonary Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. 5Division of Cell Biology, Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Email: [email protected]

  •  Accepted: 03 April 2012
  •  Published: 29 April 2012

Abstract

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.