Effect of P2X4R on airway inflammation and airway remodeling in allergic airway challenge in mice

Abstract

P2X4 receptor (P2X4R) is the most widely expressed subtype of the P2XRs in the purinergic receptor family. Adenosine triphosphate (ATP), a ligand for this receptor, has been implicated in the pathogenesis of asthma. ATP-P2X4R signaling is involved in pulmonary vascular remodeling, and in the proliferation and differentiation of airway and alveolar epithelial cell lines. However, the role of P2X4R in asthma remains to be elucidated. This aim of the present study was to investigate the effects of P2X4R in a murine experimental asthma model. The asthmatic model was established by the inhalation of ovalbumin (OVA) in BALB/c mice. The mice were treated with P2X4R-specific agonists and antagonists to investigate the role of this receptor in vivo. Pathological changes in the bronchi and lung tissues were examined using hematoxylin and eosin staining, Masson's trichrome staining and Alcian blue staining. The inflammatory cells in the bronchoalveolar lavage fluid were counted, and the expression levels of P2X4R, α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were detected using western blotting. In the OVA-challenged mice, inflammation, infiltration, collagen deposition, mucus production, and the expression levels of P2X4R and PCNA were all increased; however, the expression of α-SMA was decreased, compared with the mice in the control group. Whereas treatment with the P2X4R agonist, ATP, enhanced the allergic reaction, treatment with the P2X4R antagonist, 5-BDBD, attenuated the allergic reaction. The results suggested that ATP-P2X4R signaling may not only contribute to airway inflammation, but it may also contribute to airway remodeling in allergic asthma in mice.

Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

“…P2X4 receptors and related purinergic mechanisms involved in T cell migration may be promising therapeutic targets in lung transplantation, as suggested by previous work showing that P2X receptor antagonists could dramatically improve long-term graft survival in a mouse lung transplant model (52). Future studies will be needed to evaluate the pharmacokinetics of 5-BDBD, to refine currently used drug regimens (53,54), and to study the efficacy of this and future P2X4 receptor antagonists in the prevention of chronic lung allograft rejection.…”

“…Briefly, recipients were treated with the P2X4 inhibitor 5-BDBD (4.25 mg/kg, i.p.) or DMSO (vehicle control) 24 hours before and immediately after transplantation (53,54,57). Donor mice were treated with a single dose of 5-BDBD or DMSO 20 minutes prior to surgery.…”

P2X4: A fast and sensitive purinergic receptor

“…It is elevated in asthmatic patients and in a mouse model of asthmatic disease [108] . In the mouse model of asthma, P2X4 antagonists can be used to efficiently alleviate many of the symptoms: eosinophilia, inflammation, mucus production, and cellular infiltration in the airway [108] , [109] . P2X4-deficient mice are also less prone to Th2 responses, the same can be observed in mice which received an adoptive transfer of P2X4-deficient bone marrow cells [108] .…”

In Silico Analysis of FDA Drugs as P2X4 Modulators for the Treatment of Alcohol Use Disorder

“…activation in the neuroinflammatory mechanism, pointing out the pharmacological blockade of the receptor as a potential treatment of chronic neuropathic pain and in neuroprotection, [34,35] as well as possibly in other types of chronic pain and inflammatory pain. [6,34,[36][37][38][39][40][41] Therefore, the compounds reported in this study could be analyzed as a potential option for theses diseases.…”