The role of P2X7 purinergic receptors in inflammatory and nociceptive changes accompanying cyclophosphamide‐induced haemorrhagic cystitis in mice

Abstract

BACKGROUND AND PURPOSEATP 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. EXPERIMENTAL APPROACHEffects 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. KEY RESULTSPretreatment 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-1b and TNF-a. Finally, P2X7 receptors were markedly up-regulated in the bladders of mice with cyclophosphamide-induced HC. CONCLUSIONS AND IMPLICATIONSP2X7 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. Abbreviations

Repeated Cold Stress Reduces Cyclophosphamide-Induced Cystitis/Bladder Pain and Macrophage Activity in Mice

“…administration of CPA at 400 mg/kg is in agreement with the previous evidence for macrophage accumulation in the bladder tissue after CPA at 300 mg/kg [13], and suggests the critical role of macrophages in the bladder pain, but not cystitis itself, in this animal model. It is also consistent with our recent report indicating that the CPA-induced bladder pain, but not cystitis itself, involves the activation of RAGE by endogenous high mobility group box 1 [11], one of damage-associated molecular patterns, which can be secreted by activated macrophages [14].…”

“…In addition, it is noteworthy that the CPA-induced bladder pain, but not bladder swelling, was prevented by macrophage depletion with liposomal clodronate in our ongoing study (data not shown). The mechanisms by which CPA treatment activates macrophages remain unknown, whereas there is evidence that endogenous ATP released from the urothelial cells might contribute to macrophage infiltration in the bladder tissue [13]. Considering the decrease in LPS-induced cytokine production by peritoneal macrophages from RC-stressed mice, RC stress appears to reduce the macrophage activity, leading to the decreased bladder pain/referred hyperalgesia in response to CPA.…”

“…The CPA-treated animals appear to mimic many symptoms including bladder pain in patients with interstitial cystitis, which become worse during periods of stress [12]. Given the evidence that CPA treatment causes macrophage accumulation in the bladder tissue of the mouse [13], we examined and characterized the effect of RC stress on the CPA-induced cystitis and bladder pain in mice, in relation to the activity of macrophages.…”

Differential expression of ATP-gated P2X receptors in DRG between chronic neuropathic pain and visceralgia rat models

“…Other research suggested that the expression of P2X4 receptor in the dorsal horn of the thoracic cord increased in the visceral pain model [23] and that the expressions of P2X7 receptors were increased in the jejunum of postinflammatory visceral hypersensitivity mice [24] and haemorrhagic cystitis mice model [25], respectively. Our results showed that except the P2X2 and P2X3 receptors, the expressions of P2X4 and P2X7 receptors increased obviously in visceral pain model.…”

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

“…Furthermore, a number of these studies also had supporting P2X7 KO mouse data alongside P2X7 antagonist data, further implicating P2X7 in a number of disease processes. These include models of hemorrhagic cystitis (Martins et al, 2012), glomerulonephritis (Taylor et al, 2009b), hypertension and renal injury , lung inflammation (Lucattelli et al, 2011), allergic airway inflammation , pancreatitis (Hoque et al, 2011), and graft-versus-host disease (Wilhelm et al, 2010).…”