title: Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis.
abstract: OBJECTIVE
  To investigate the presence of progesterone receptors and the extent and type of degranulation exhibited by the increased numbers of mast cells (MCs) found in interstitial cystitis (IC), a painful bladder disorder which occurs almost exclusively in women, worsens perimenstrually and is characterized by increased numbers of oestradiol receptor (OR)-positive MCs.
  
  
  METHODS
  The state of MC degranulation was analysed blindly using electron microscopy of bladder biopsies from 26 patients with IC and six control patients which included five women with incontinence, with none of the established characteristics of IC, and one man with transitional carcinoma of the bladder. Emphasis was placed on preserving the secretory granule ultrastructure. The presence of progesterone receptors (PRs) in five patients with IC and three controls was investigated using commercially available antibodies against PRs.
  
  
  RESULTS
  Over 85% of bladder MCs expressed high affinity PRs, but the number of PR-positive MCs in patients with IC did not differ significantly from that of controls despite the overall increase in MCs seen in IC. MCs were activated to various degrees and were often near to neuronal processes. The secretory granule content of MCs from patients with IC was in different stages of dissolution, ranging from heterogeneous loss of electron density to the appearance of crystalline substructure and target forms containing only remnants of the original material. Typical degranulation by compound exocytosis was not observed. MCs from control patients contained secretory granules with mostly intact, electron-dense granules.
  
  
  CONCLUSIONS
  These findings indicate that the symptoms of IC may depend on an imbalance of the relative number of oestrogen receptors (ORs) to PRs on bladder MCs resulting in a 'progesterone deficient' state. This possibility is strengthened by demonstration that oestradiol augments the secretion of MC histamine in response to the neuropeptide substance P, which is pro-inflammatory, nociceptive and overexpressed in bladders with IC. Intragranular activation of bladder MCs is a characteristic pathological finding in patients with IC. The lack of extensive degranulation, typically seen in anaphylaxis, may indicate a unique mode of stimulation and/or differential release of mediators.
authors.affiliation: Department of Pharmacology, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: R
authors.initials: R
authors.lastname: Letourneau
authors.forename: X
authors.initials: X
authors.lastname: Pang
authors.forename: G R
authors.initials: GR
authors.lastname: Sant
authors.forename: T C
authors.initials: TC
authors.lastname: Theoharides
mesh_terms: D000328:Adult; D015550:Cell Degranulation; D018856:Cystitis, Interstitial / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis*; D001743:Urinary Bladder / Q000737:chemistry / Q000294:innervation / Q000473:pathology*
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone