title: Role of CXCR2 and TRPV1 in functional, inflammatory and behavioural changes in the rat model of cyclophosphamide-induced haemorrhagic cystitis.
abstract: OBJECTIVE
  Cyclophosphamide induces urotoxicity characterized by the development of cystitis, which involves bladder overactivity and inflammation. Here, we investigated the roles of chemokine receptor 2 (CXCR2) and transient receptor potential vanilloid 1 (TRPV1) channels in a rat model of cyclophosphamide-induced cystitis.
  
  
  METHODS
  Cystitis induced by cyclophosphamide in rats was assessed by gross morphology, histology and immunohistochemistry of bladder tissue. mRNA for CXCR2 and TRPV1 channels were measured by RT-PCR. Nociceptive responses in paw and abdomen, along with cystometric measures were recorded.
  
  
  RESULTS
  Cyclophosphamide, i.p., induced pain behaviour, bladder inflammation and voiding dysfunction. The CXCR2 antagonist, SB225002, the TRPV1 channel antagonist, SB366791 or their combination reduced the mechanical hypersensitivity of paw and abdominal area and nociceptive behaviour after cyclophosphamide. Cyclophosphamide-induced cystitis was characterized by haemorrhage, oedema, neutrophil infiltration and other inflammatory changes, which were markedly decreased by the antagonists. Up-regulation of CXCR2 and TRPV1 mRNA in the bladder after cyclophosphamide was inhibited by SB225002, SB366791 or their combination. Expression of CXCR2 and TRPV1 channels was increased in the urothelium after cyclophosphamide. Bladder dysfunction was shown by increased number of non-voiding contractions (NVCs) and bladder pressures and a reduction in bladder capacity (BC), voided volume (VV) and voiding efficiency (VE). SB225002 or its combination with SB366791 reduced bladder pressures, whereas SB225002, SB366791 or their combination increased BC, VV and VE, and also reduced the number of NVCs.
  
  
  CONCLUSIONS
  CXCR2 and TRPV1 channels play important roles in cyclophosphamide-induced cystitis in rats and could provide potential therapeutic targets for cystitis.
authors.affiliation: Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Fabiana N
authors.initials: FN
authors.lastname: Dornelles
authors.forename: Edinéia L
authors.initials: EL
authors.lastname: Andrade
authors.forename: Maria M
authors.initials: MM
authors.lastname: Campos
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D001522:Behavior, Animal / Q000187:drug effects*; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006474:Hemorrhagic Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D009504:Neutrophils / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001743:Urinary Bladder / Q000473:pathology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016207:Cytokines; D023063:Receptors, Interleukin-8B; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D003520:Cyclophosphamide; D009195:Peroxidase
keywords: CXCR2 receptors; Cyclophosphamide-induced cystitis; TRPV1 channels; bladder inflammation; pain behaviour; voiding dysfunction