Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction M. Dib, X. Zhao, X. D. Wang* and R. Andersson Department of Surgery, Lund University Hospital and *Department of BioScience, AstraZeneca R & D, Lund, Sweden Correspondence to: Dr R. Andersson, Department of Surgery, Lund University Hospital, S-221 85 Lund, Sweden e-mail: roland.andersson@kir.lu.se) Background: Activated mast cells can produce and release a number of in¯ammatory mediators involved in the pathophysiology of acute conditions. The aim of the present study was to evaluate the roleofactivatedtissuemastcellsinthepathogenesisofmultipleorgandysfunctionsyndromefollowing acutepancreatitisAP). Methods: APwasinducedbytheintraductalinfusionof5percentsodiumtaurodeoxycholateintherat. Some 30 min before induction of AP, a mast cell stabilizer sodium cromoglycate SCG)) or antihistamines pyrilamine, cyproheptadine, meclizine and amitriptyline) were administered intra- peritoneally. Plasma exudation of radiolabelled albumin, histamine, myeloperoxidase MPO), monocyte chemoattractant protein MCP) 1 and adhesion molecules platelet endothelial cell adhesion molecule PECAM)1andL-selectin)weremeasured. Results: The mast cell stabilizer signi®cantly reduced plasma exudation in the pancreas, colon and lungs P < 0´05), decreased the release of histamine at 1 h P < 0´05), and reduced MPO activity and MCP-1 levels in the colon and lungs P < 0´05) but not in the pancreas. Expression of PECAM-1 and L-selectinontotalcirculatingleucocytesinratswithAPandSCGpretreatmentdidnotdifferfromthat in sham controls, while levels in animals that had AP and saline pretreatment were half of those seen followingshamoperation. Conclusion: ActivationofmastcellsafterinductionofAPisinvolvedinthedevelopmentofendothelial barrierdysfunctioninboththepancreasandextrapancreaticorgans/tissues,particularlyinthelungsand colon.Thismay,atleastpartly,contributetothesequentialdevelopmentofmultipleorgandysfunction andorgan/tissue-speci®cendothelialbarrierdysfunction. Paper accepted 2 October 2001 British Journal of Surgery 2002, 89, 172±178 Introduction Acute pancreatitis AP) is a common disorder with a yearly incidence of 50±500 attacks per million inhabitants 1 . Acute lung injury and pancreatic sepsis, associated with increased permeability and enteric bacterial translocation into extra- intestinal sites and the systemic circulation gut origin sepsis) 2,3 , are major contributory factors to death and morbidity in severe AP. Underlying mechanisms for the local initiating events in the pancreas, the systemic dissemination of the in¯ammatory response and remote organ dysfunction in AP are still not fully elucidated, but involve a variety of cells and mediators including cytokines. Mast cells are found closely apposed to the vasculature in essentially all tissues. Once activated, mast cells release preformed cytokines, histamine and serotonin as well as newly synthesized platelet activating factor, leukotrienes and possibly other mediators 4,5 . Thus, mast cells potentially play a central role in the initiation of the in¯ammatory response 4 characterized by microvascular changes, includ- ing increased vascular permeability and leucocyte accumu- lation 6 . The objective of the present study was to determine the effects of mast cells in vivo on: 1) local pancreatic) injury; 2) multiple organ/tissue injury, e.g. in the lungs and the gut; 3) leucocyte recruitment myeloperoxidase MPO)); 4) chemokine release monocyte chemoattractant protein MCP) 1); and 5) adhesion molecule expression on circulating leucocytes in severe AP. Sodium cromoglycate SCG; cromolyn) 6±10 used in this study is one of the most effective inhibitors of histamine release associated with degranulation) from activated mast cells 11 , delaying and almost entirely reducing the degranulation of mast cells 9 , Original article 172 ã 2002 Blackwell Science Ltd British Journal of Surgery 2002, 89, 172±178