Abstract. Background: Sepsis is associated with the highest risk of progression to acute lung injury or the acute respira- tory distress syndrome. Ketamine has been advocated for anesthesia in endotoxemic and other severely ill patients because it is a cardiovascular stimulant. Our study was designed to investigate the effect of ketamine on the endo- toxin-induced acute lung injury in vivo. Materials and methods: Adult male Wistar rats were ran- domly divided into 6 groups: saline controls; rats challenged with endotoxin (5 mg/kg) and treated with saline; challenged with endotoxin (5 mg/kg) and treated with ketamine (0.5 mg/ kg); challenged with endotoxin (5 mg/kg) and treated with ketamine (5 mg/kg); challenged with endotoxin (5 mg/kg) and treated with ketamine (50 mg/kg); saline injected and treated with ketamine (50 mg/kg). TNF-a, IL-6 and NF- kappa B were investigated in the tissues of the lung after 2 h. Myeloperoxidase (MPO) activity and wet/dry weight ratio were investigated 6 h later. Results: We demonstrated that intravenous administration of endotoxin could provoke significant lung injury, which was characterized by increase of MPO activity and wet/dry weight ratio, TNF-a and IL-6 expression and NF-kappa B activation. Ketamine (5, 50 mg/kg) inhibited endotoxin- induced NF-kappa B activation. Ketamine only at a dose of 50 mg/kg inhibited TNF-a and IL-6 production, and decreased MPO activity and wet/dry weight ratio after endo- toxin challenge. Conclusions: Ketamine, only at a supra-anesthetic dosage, could inhibit endotoxin-induced pulmonary inflammation in vivo. Key words: Endotoxin – NF-kappa B – TNF-a – Lung – Ketamine – Rats Inflamm. res. 54 (2005) 133– 137 1023-3830/05/030133-05 DOI 10.1007/s00011-004-1334-5 Introduction Acute respiratory distress syndrome (ARDS) is a common, devastating clinical syndrome of acute lung injury (ALI) that affects both medical and surgical patients. Until recently, most studies of acute lung injury and the acute respiratory distress syndrome have reported a mortality rate of 40 to 60 percent [1 – 3]. Sepsis is associated with the highest risk of progression to acute lung injury or the acute respiratory distress syn- drome, at approximately 40 percent [4]. The intravenous anesthetic ketamine has been advocated for use in endotox- emic or severely ill patients because of its stimulatory effects on the cardiovascular system [5]. Further it also suppresses lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-a) production at concentrations > 20 mg/mL, and significantly suppresses both LPS-induced and TNF-induced interleukin 6 (IL-6) and IL-8 production at concentrations > 100 mg/mL in human whole blood in vitro [6]. It is also demonstrated that ketamine has the ability to suppress LPS- induced TNF-a and NF-kappa B activation in peripheral blood mononuclear cells (PBMC) [7]. Since TNF-a, IL-6, and NF-kappa B are known to be very important inflamma- tory mediators in the pathogenesis of LPS-induced acute lung injury [8], and ketamine seems to have a powerful inhibitory effect on these inflammatory mediators, therefore this study was intended to investigate whether ketamine could suppress endotoxin-induced acute lung injury in vivo. Materials and methods Animals and experiment protocol Adult male Wistar rats (50 days old), which were free of pathogens, were purchased from Shanghai Animal Center, Shanghai, China. The rats were exposed daily to 12 h of light and 12 h of darkness. Rodent food and water were provided freely. The experimental protocol fol- lowed institutional criteria for the care and use of laboratory animals in research. © Birkhäuser Verlag, Basel, 2005 Inflammation Research Large dose ketamine inhibits lipopolysaccharide-induced acute lung injury in rats J. Yang 1 , W. Li 1 , M. Duan 1 , Z. Zhou 1 , N. Lin 1 , Z. Wang 2 , J. Sun 1 and J. Xu 1 1 School of Medicine, Nanjing University and Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, China, Fax: ++86 25 84806839, e-mail: zbfcj@hotmail.com 2 Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China Received 27 August 2004; returned for revision 11 November 2004; accepted by A. Falus 15 November 2004 Correspondence to: J. Xu