title: The role of P2X7 purinergic receptors in inflammatory and nociceptive changes accompanying cyclophosphamide-induced haemorrhagic cystitis in mice.
abstract: OBJECTIVE
  ATP is released in response to cellular damage, and P2X7 receptors have an essential role in the onset and maintenance of pathological changes. Haemorrhagic cystitis (HC) is a well-known adverse effect of therapy with cyclophosphamide used for the treatment of many solid tumours and autoimmune conditions. Here we have evaluated the role of P2X7 receptors in a model of HC induced by cyclophosphamide.
  
  
  METHODS
  Effects of pharmacological antagonism or genetic deletion of P2X7 receptor on cyclophosphamide-induced HC in mice was assessed by nociceptive and inflammatory measures. In addition, the presence of immunoreactive P2X7 receptors was assessed by immunohistochemistry.
  
  
  RESULTS
  Pretreatment with the selective P2X7 receptor antagonist A-438079 or genetic ablation of P2X7 receptors reduced nociceptive behaviour scores in the HC model. The same strategies decreased both oedema and haemorrhage indices, on macroscopic or histological evaluation. Treatment with A-438079 decreased the staining for c-Fos in the lumbar spinal cord and brain cortical areas. Treatment with A-438079 also prevented the increase of urinary bladder myeloperoxidase activity and macrophage migration induced by cyclophosphamide and reduced the tissue levels of IL-1β and TNF-α. Finally, P2X7 receptors were markedly up-regulated in the bladders of mice with cyclophosphamide-induced HC.
  
  
  CONCLUSIONS
  P2X7 receptors were significantly involved in a model of HC induced by cyclophosphamide. Pharmacological inhibition of these receptors might represent a new therapeutic option for this pathological condition.
authors.affiliation: Faculdade de Medicina, PUCRS, Porto Alegre, RS, Brazil.
authors.forename: J P
authors.initials: JP
authors.lastname: Martins
authors.forename: R B M
authors.initials: RB
authors.lastname: Silva
authors.forename: R
authors.initials: R
authors.lastname: Coutinho-Silva
authors.forename: C M
authors.initials: CM
authors.lastname: Takiya
authors.forename: A M O
authors.initials: AM
authors.lastname: Battastini
authors.forename: F B
authors.initials: FB
authors.lastname: Morrone
authors.forename: M M
authors.initials: MM
authors.lastname: Campos
mesh_terms: D000818:Animals; D002465:Cell Movement; D003520:Cyclophosphamide / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D016762:Genes, fos; D006470:Hemorrhage / Q000139:chemically induced* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D008297:Male; D015080:Mesna / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D059225:Nociception / Q000502:physiology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D016207:Cytokines; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D003520:Cyclophosphamide; D015080:Mesna