ATP-P2X4Rs信号通路在哮喘气道炎症和气道重塑中的作用及机制

Asthma is a chronic inflammatory airway disease characterized by hyperresponsiveness and airway remodeling to nonspecific stimuli. Adenosine triphosphate (ATP) has been implicated as an important mediator and "danger signal" in acute and chronic inflammation and can be released in large amounts cells from various cell types after cellular stress or tissue injury. Several studies demonstrated that ATP is a ligand of P2X4R, and ATP-mediated P2X4Rs signaling pathway contributes to immunoregulation of neuritis. P2X4Rs is expressed in lung tissue and immunocyte. So we suppose that ATP-mediated P2X4Rs signaling pathway may contribute to airway inflammation and remodeling in asthma. It will be confirmed by the follows. 1.To confirm that ATP-mediated P2X4Rs signaling pathway participates in the pathogenesis of asthma. 2.To confirm that ATP-mediated P2X4Rs signaling pathway contributes to airway inflammation by regulating Th1/Th2 disequilibrium. 3. To confirm that ATP-mediated P2X4Rs signaling pathway contributes to airway remodeling of airway smooth muscle cell and epithelium tissue. 4.To indicate that the effect and mechanism of ATP-P2X4R signaling pathway in airway inflammation and remodeling in asthma. The study will supply and consummate the pathogenesis of asthma, providing theory basis for developing new treatment strategy of asthma.

哮喘的本质是气道慢性炎症，并在此基础上出现气道高反应性和气道重塑。ATP是急慢性炎症过程中一个重要的调节器和危险信号，ATP介导的慢性气道炎症在哮喘发病中的作用日益受到重视。已有研究表明，ATP是嘌呤碱受体P2X4Rs的配体，ATP-P2X4Rs通路参与神经炎症时的免疫调节反应，且P2X4Rs在肺组织及免疫细胞中有表达。有鉴于此，我们提出假说: ATP-P2X4Rs信号通路参与哮喘发病的气道炎症及气道重塑。拟通过以下四方面证明该假设：1、明确ATP-P2X4Rs信号通路参与哮喘发病。2、确定ATP-P2X4Rs信号通路调控Th1/Th2平衡失调参与哮喘气道炎症。3、确定ATP-P2X4Rs信号通路参与哮喘气道平滑肌细胞及上皮细胞重塑过程。4、揭示ATP-P2X4Rs信号通路在哮喘气道炎症和气道重塑中的作用及机制。本研究将补充和完善支气管哮喘发病机制，为开辟哮喘治疗新途径提供理论依据。

哮喘的本质是气道慢性反应性炎症，并在此基础上出现气道高反应性和气道重塑，气道重塑是哮喘的重要特征之一，是不可逆性气流阻塞和气道高反应性的重要病理基础，该病已经发展成为世界第二大致死性和致残性疾病。P2X4R是分布最广泛的P2XR亚型，其配体ATP已被证实与哮喘发病有关。P2X4R信号通路还参与肺动脉高压时肺血管的重构和气道及肺泡上皮细胞系的增殖与分化。然而，P2X4R是否参与过敏性支气管哮喘发病过程尚不清楚。本研究通过制作过敏性哮喘小鼠模型，明确P2X4R是否参与过敏性支气管哮喘发病，并深入探讨其在过敏性支气管哮喘气道炎症及气道重塑中的作用及机制。研究结果表明，过敏性支气管哮喘小鼠肺组织及支气管肺泡灌洗液中P2X4R的表达较对照组明显增高；给予P2X4R的特异性拮抗剂5-BDBD后，通过抑制p38MAPK-NF-κB通路明显减轻了哮喘气道炎症及气道重塑的发生。本研究结果明确了ATP-P2X4R信号通路参与哮喘发病，并深入揭示了ATP-P2X4R信号通路参与哮喘气道炎症和气道重塑的过程及机理。有利于进一步补充和完善支气管哮喘的病理生理学发病机制，从而为寻找在此环节上更好的进行干预治疗的靶点提供理论依据。