A key role of neurokinin 1 receptors in acute pancreatitis and associated lung injury Hon Yen Lau 1 , Fei Ling Wong 1 , Madhav Bhatia * Department of Pharmacology, National University of Singapore, Singapore Received 26 November 2004 Available online 15 December 2004 Abstract Earlier studies have shown that mice deficient in NK1 receptors or its ligand, substance P, are protected against acute pancreatitis and associated lung injury. In the current study, the protective effect of NK1 receptor blockage against acute pancreatitis and asso- ciated lung injury was investigated, using a specific receptor antagonist, CP-96345. Acute pancreatitis was induced in mice by intra- peritoneal (i.p.) injections of caerulein. Substance P levels in plasma, pancreas, and lungs were found to be elevated in a caerulein dose-dependent manner. Mice treated with CP-96345, either prophylactically, or therapeutically, were protected against acute pan- creatitis and associated lung injury as evident by attenuation in plasma amylase, pancreatic and pulmonary myeloperoxidase activ- ities, and histological evidence of pancreatic and pulmonary injuries. Pulmonary microvascular permeability was also reduced as a result of CP-96345 treatment. These results point to a key role of NK1 receptors in acute pancreatitis and associated lung injury. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Acute pancreatitis; Substance P; CP-96345; Caerulein Acute pancreatitis (AP) is a common clinical condi- tion, whose incidence has been increasing over recent years [1]. Most cases are secondary to gallstones or ex- cess alcohol consumption. Irrespective of the cause, acti- vation of digestive enzymes within pancreatic acinar cells is thought to be a critical initiating event [1,2]. Pan- creatic damage then leads to a localized and a subse- quent systemic inflammatory response. If the latter is marked, it may lead to leukocyte-mediated distant or- gan damage and the development of multiple organ dys- function syndrome (MODS), which is responsible for the majority of deaths in this condition [1]. Substance P and neurokinin-A (NKA) are neuropep- tide products of the preprotachykinin-A (PPT-A) gene. PPT-A mRNAs code for the synthesis of both substance P and neurokinin A. Substance P is released from nerve endings in many tissues. Subsequent to its release, sub- stance P binds primarily, but not exclusively, to neuro- kinin-1 receptors (NK1R) on the surface of effector cells and, in addition to being a mediator of pain, acts as a pro-inflammatory mediator in many inflammatory states including asthma, immune-complex-mediated lung injury, experimental arthritis, and inflammatory bowel disease [1–6]. NKA binds primarily to neuroki- nin-2 receptors (NK2R). Substance P has been detected within the pancreas and it has been suggested that sub- stance P may act as a neurotransmitter for sensory affer- ent nerves in the pancreas. Receptors for substance P have also been detected on guinea-pig pancreatic acinar cells and this neuropeptide acts as a secretagogue, stim- ulating amylase secretion from acinar cells via a G protein-, phospholipase-, inositol phosphate-, and calci- um-mediated mechanism in that species. Rat pancreatic acinar cells apparently do not express receptors for sub- stance P and the neuropeptide does not stimulate en- zyme secretion from rat acinar cells. By contrast, 0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.12.030 * Corresponding author. Fax: +65 6873 7690. E-mail address: mbhatia@nus.edu.sg (M. Bhatia). 1 These two authors contributed equally to the work. www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 327 (2005) 509–515 BBRC