title: Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation.
abstract: BACKGROUND
  In general, inflammation plays a role in most bladder pathologies and represents a defense reaction to injury that often times is two edged. In particular, bladder neurogenic inflammation involves the participation of mast cells and sensory nerves. Increased mast cell numbers and tryptase release represent one of the prevalent etiologic theories for interstitial cystitis and other urinary bladder inflammatory conditions. The activity of mast cell-derived tryptase as well as thrombin is significantly increased during inflammation. Those enzymes activate specific G-protein coupled proteinase-activated receptors (PAR)s. Four PARs have been cloned so far, and not only are all four receptors highly expressed in different cell types of the mouse urinary bladder, but their expression is altered during experimental bladder inflammation. We hypothesize that PARs may link mast cell-derived proteases to bladder inflammation and, therefore, play a fundamental role in the pathogenesis of cystitis.
  
  
  RESULTS
  Here, we demonstrate that in addition to the mouse urinary bladder, all four PA receptors are also expressed in the J82 human urothelial cell line. Intravesical administration of PAR-activating peptides in mice leads to an inflammatory reaction characterized by edema and granulocyte infiltration. Moreover, the inflammatory response to intravesical instillation of known pro-inflammatory stimuli such as E. coli lipopolysaccharide (LPS), substance P, and antigen was strongly attenuated by PAR1-, and to a lesser extent, by PAR2-deficiency.
  
  
  CONCLUSIONS
  Our results reveal an overriding participation of PAR1 in bladder inflammation, provide a working model for the involvement of downstream signaling, and evoke testable hypotheses regarding the role of PARs in bladder inflammation. It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestations of cystitis.
authors.affiliation: Department of Physiology, The University Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. ricardo-saban@ouhsc.edu
authors.forename: Ricardo
authors.initials: R
authors.lastname: Saban
authors.forename: Michael R
authors.initials: MR
authors.lastname: D'Andrea
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hurst
authors.forename: Carole A
authors.initials: CA
authors.lastname: Davis
authors.forename: Cindy
authors.initials: C
authors.lastname: Simpson
authors.forename: Marcia R
authors.initials: MR
authors.lastname: Saban
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D002460:Cell Line; D003556:Cystitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004487:Edema / Q000139:chemically induced; D006098:Granulocytes / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044463:Receptor, PAR-1 / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D013373:Substance P; D001743:Urinary Bladder / Q000378:metabolism; D019459:Urothelium / Q000166:cytology / Q000378:metabolism
chemical_list: D000941:Antigens; D008070:Lipopolysaccharides; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D044462:Receptors, Proteinase-Activated; D013373:Substance P