MAST CELL INVOLVEMENT IN INTERSTITIAL CYSTITIS: A REVIEW OF HUMAN AND EXPERIMENTAL EVIDENCE THEOHARIS C. THEOHARIDES, DURAISAMY KEMPURAJ, AND GRANNUM R. SANT ABSTRACT Interstitial cystitis (IC) is a heterogeneous syndrome of unknown etiology. Altered bladder glycosaminogly- cans lining and bladder mastocytosis have been documented in IC. The objective of this article is to critically examine the published data on bladder mastocytosis in clinical, experimental, and animal studies, with particular emphasis on morphologic evidence of mast cell increase and activation. The literature on bladder mastocytosis and mast cell activation in IC is critically reviewed with particular reference to staining methodology, tryptase immunoreactivity, and electron microscopy. Data from humans and animal models of IC are included. Mastocytosis in IC is best documented by tryptase immunocytochemical staining. Standard surgical stains such as Giemsa and toluidine blue routinely underestimate the degree of mastocytosis. Mast cells are 6- to 8-fold higher in the detrusor compared with controls in “classic IC,” and 2- to 3-fold higher in “nonulcerative” IC. Detrusor mastocytosis occurs in both classic and nonulcer IC. Mucosal mast cell increase is present in nonulcerative IC. Mast cell activation without typical exocytosis occurs in the mucosa and submucosa. Activation of mast cells, irrespective of bladder location or degree of mastocytosis, is significant. Mast cell-derived vasoactive and proinflammatory molecules may contribute to the pathogenesis of IC. UROLOGY 57 (Suppl 6A): 47–55, 2001. © 2001, Elsevier Science Inc. I nterstitial cystitis (IC) is a bladder syndrome characterized by urinary urgency, frequency, su- prapubic and pelvic pain, and dyspareunia. 1,2 The pathologic features of IC on light microscopy in- clude edema, vasodilatation, and suburothelial hemorrhages. 3,4 Ulcers are present in 10% of IC patients (“classic IC”). Neither symptom severity 5 nor cytoscopic findings under anesthesia 6 parallel the degree of bladder inflammation. 5–7 The exact etiology and pathogenesis of IC is un- clear. IC is currently regarded as a heterogeneous syndrome. The 2 main etiologic theories for IC are that of a defect in bladder cytoprotection, 8 even though it has recently been challenged, 9 and in- creased bladder mast cells, 10 first suggested by Sim- mons and Bunce. 11 Defective cytoprotection with increased urothelial permeability may allow mast cell secretagogues and potassium to penetrate the normally impermeable bladder lining and activate bladder mast cells and sensory nerves. 12,13 MAST CELLS Mast cells arise from the bone marrow and are known to participate in allergic and type 1 hyper- sensitivity reactions. 14 Mast cells are also triggered by nonimmunologic stimuli (Table I): kinins, neu- ropeptides such as neurotensin (NT), 15 somatosta- tin (SRIF), 16 substance P (SP), 17 neuropeptide Y, 18 and the neurotransmitter acetylcholine (ACh). 19 Mast cell mediators 20,21 are either preformed gran- ule-stored molecules (eg, heparin, histamine, pro- teases, phospholipases, chemotactic substances, and cytokines), or synthesized de novo (eg, cyto- kines, especially interleukin [IL]-6), 14 leuko- trienes (LTC 4 ), prostaglandins (PG; eg, PGD 2 ), platelet-activating factor (PAF), and nitric oxide (NO). 22 Mast cells release vasoactive intes- tinal peptide (VIP) 23 and tumor necrosis factor (TNF)-, both of which are potent vasodilatory molecules. 14 These mast cell products may effect a From the Departments of Pharmacology and Experimental Ther- apeutics, Internal Medicine, and Urology, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts, USA Aspects of this work were supported in part by grants DK42409 and DK44816 from the NIH/NIDDK, from Kos Pharmaceuticals (Miami, FL) and Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA), as well as pilot grants from the Inter- stitial Cystitis Association (New York, NY). Reprint requests: Theoharis C. Theoharides, PhD, MD, Depart- ment of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111. E-mail: theoharis.theoharides@ tufts.edu © 2001, ELSEVIER SCIENCE INC. 0090-4295/01/$20.00 ALL RIGHTS RESERVED PII S0090-4295(01)01129-3 47