Downloaded from http://journals.lww.com/shockjournal by BhDMf5ePHKbH4TTImqenVCbF2BRbWAbdjmHCrqobKSzI129z+3SSECiAHsXIuBOm on 12/08/2019 Copyright @ 200 by the Shock Society. Unauthorized reproduction of this article is prohibited. 7 TREATMENT WITH H 2 S-RELEASING DICLOFENAC PROTECTS MICE AGAINST ACUTE PANCREATITIS–ASSOCIATED LUNG INJURY Madhav Bhatia,* Jenab N. Sidhapuriwala,* Anna Sparatore, † and Philip K. Moore* *Department of Pharmacology and Cardiovascular Biology Research Group, National University of Singapore; and † Department of Chemistry, University of Milan, Italy Received 26 Feb 2007; first review completed 14 Mar 2007; accepted in final form 26 Mar 2007 ABSTRACT—Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Hydrogen sulfide (H 2 S) is a naturally occurring gas that has been shown to be a potent vasodilator. Diclofenac is a nonsteroidal anti-inflammatory drug and has been shown to have anti-inflammatory, analgesic, and antipyretic activity. ACS15 is an H 2 S-releasing derivative of diclofenac. Little is known about its effectiveness as an anti-inflammatory drug. In this report, we describe the effect of diclofenac and its H 2 S-releasing derivative on acute pancreatitis and associated lung injury in the mouse. Acute pancreatitis was induced in mice by hourly i.p. injections of cerulein. Diclofenac and ACS15 were administered either 1 hour before or 1 hour after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury was assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic myeloperoxidase activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitisYassociated lung injury was assessed by neutrophil sequestration in the lungs (lung myeloperoxidase activity) and by histological examination of lung sections. ACS15, given prophylactically and therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of H 2 S-releasing nonsteroidal anti-inflammatory drugs as potential treatments for pancreatitis-associated lung injury. KEYWORDS—Cerulein, myeloperoxidase, inflammation, hydrogen sulfide INTRODUCTION Acute pancreatitis is a common clinical condition, the incidence of which has been increasing over recent years (1Y4). Approximately 25% of patients suffer a severe attack, and between 30% and 50% of these will die (1Y4). The exact mechanisms by which diverse etiological factors induce an attack of acute pancreatitis are still unclear, but once the disease process is initiated, common inflammatory and repair pathways are invoked. If this inflammatory reaction is very pronounced, it leads to a systemic inflammatory response syndrome (SIRS), and it is this systemic response that is responsible for most morbidity and mortality (1Y4). Systemic leukocyte activation is a direct consequence of a SIRS, and if excessive, it can lead to distant organ damage and multiple organ dysfunction syndrome (MODS) (1Y5, 18). Lung injury that manifests itself clinically as acute respiratory distress syndrome is a major component of MODS associated with acute pancreatitis and is associated with the morbidity and mortality in most cases of severe acute pancreatitis (1Y5, 18). Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID), and as such, a cyclooxygenase inhibitor. Non- steroidal anti-inflammatory drugs are one of the most commonly used classes of medicines. Nonsteroidal anti- inflammatory drugs are prescribed largely for their anti- inflammatory, antipyretic, and analgesic properties and are also available in over-the-counter preparations. The major drawback in the use of NSAIDs is their tendency to cause gastrointestinal (GI) toxicity. Although various approaches have been taken to produce NSAIDs with reduced GI toxicity, few have significantly reduced the incidence of clinically significant adverse reactions (perforation or hemorrhage). The ability of an NSAID to cause gastric damage correlates well with its ability to suppress gastric prostaglandin synthesis (by cyclooxygenase 1) (19). Hydrogen sulfide (H 2 S) has recently been identified as a biological mediator (6Y8, 18, 22). It exhibits potent vaso- dilator activity most probably via vascular smooth muscle K ATP channels. Recent studies have shown an important role of H 2 S in several models of inflammation (6, 7, 14) such as acute pancreatitis and associated lung injury (9), carrageenan- induced hindpaw edema (10), LPS-induced endotoxemia (17), and cecal ligation and punctureYinduced sepsis (23, 24). Recently, an H 2 S-releasing derivative of diclofenac (ACS15-2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4- (3H-1,2-dithiole-3-thione-5-yl)-phenyl ester has been developed by CTG Pharma (Milan, Italy). Because H 2 S is recognized as a critical mediator of GI mucosal defense, an H 2 S-releasing NSAID such as ACS15 is likely to cause significantly less GI damage than the parent NSAID, although no study has as yet been reported on its effect on inflammation. In this article, we report results of our studies on the effect of treatment of mice with diclofenac and the cor- responding H 2 S-releasing derivative ACS15 on the severity of 84 SHOCK, Vol. 29, No. 1, pp. 84Y88, 2008 Address reprint requests to Madhav Bhatia, PhD, Department of Pharmacology, Yong Loo Lin School of Medicine Centre for Life Sciences, National University of Singapore, 28 Medical Drive, Singapore 117456. E-mail: mbhatia@nus.edu.sg. This work was supported by the Office of Life Sciences Cardiovascular Biology Program (grant no. R-184Y000Y074Y712), National University of Singapore, and Biomedical Research Council (grant no. R-184Y000Y94Y305). DOI: 10.1097/shk.0b013e31806ec26 Copyright Ó 2007 by the Shock Society