This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Mikawa, K. Articles by Obara, H. Search for Related Content PubMed PubMed Citation Articles by Mikawa, K. Articles by Obara, H. Related Collections Critical Care Resuscitation Pharmacology

---

CRITICAL CARE AND TRAUMA

ONO-1714, a Nitric Oxide Synthase Inhibitor, Attenuates Endotoxin-Induced Acute Lung Injury in Rabbits

From the Department of Anesthesia & Perioperative Medicine, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, Kobe, Japan

Address correspondence and reprint requests to Dr. K. Mikawa, Department of Anesthesia & Perioperative Medicine, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, Kusunoki-cho 7, Chuo-ku, Kobe 650–0017, Japan. Address email to katzmikawa{at}yahoo.co.jp

Overproduction of nitric oxide by inducible nitric oxide synthase (iNOS) expressed in the lung is thought to play a crucial role in the pathogenesis of endotoxin-induced acute lung injury (ALI). In this two-part study, we determined whether ONO-1714, a new selective iNOS inhibitor, attenuates endotoxin-induced ALI in rabbits. For Part I of the study, a control group received IV saline and ALI was induced by IV infusion of endotoxin 5 mg/kg over 30 min in 4 groups. Three groups received either 0.1, 0.03, or 0.01 mg/kg of ONO-1714 10 min before the start of endotoxin and the fourth group received saline. For Part II of the study, ALI was induced by endotoxin infusion in all 6 groups. One group was treated with saline. The other 5 groups received ONO-1714 0.1 mg/kg at various timings (10 min before or 1, 2, 3, or 4 h after ALI induction). The lungs were mechanically ventilated with 40% oxygen for 6 h after induction of ALI. In Part I, pretreatment with 0.1 mg/kg ONO-1714 mitigated endotoxin-induced ALI. In Part II, early posttreatment (within 2 h after the insult) with ONO-1714 was as effective as pretreatment in improving oxygenation, lung mechanics, lung leukosequestration, pulmonary edema, and histological change. However, lung damage was not improved in rabbits receiving the drug 3 or 4 h after endotoxin. These data suggest that the current study is a basis for future clinical trials to elucidate whether ONO-1714 can be a promising therapeutic approach in patients with acute respiratory distress syndrome induced by endotoxin/sepsis.

IMPLICATIONS: An excess of nitric oxide is thought to play a crucial role in the pathogenesis of acute organ injury in endotoxemia. Early posttreatment with ONO-1714, a nitric oxide synthase inhibitor, attenuated physiological, biochemical, and pathological changes in endotoxin-induced acute lung injury in rabbits.

This article has been cited by other articles:

				B. P. van Putte, P. M. Cobelens, N. van der Kaaij, B. Lachmann, A. Kavelaars, C. J. Heijnen, and J. Kesecioglu Exogenous surfactant attenuation of ischemia-reperfusion injury in the lung through alteration of inflammatory and apoptotic factors J. Thorac. Cardiovasc. Surg., April 1, 2009; 137(4): 824 - 828. [Abstract] [Full Text] [PDF]

				A. Chatterjee, C. Dimitropoulou, F. Drakopanayiotakis, G. Antonova, C. Snead, J. Cannon, R. C. Venema, and J. D. Catravas Heat Shock Protein 90 Inhibitors Prolong Survival, Attenuate Inflammation, and Reduce Lung Injury in Murine Sepsis Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 667 - 675. [Abstract] [Full Text] [PDF]