细胞间粘附分子-1在间质性膀胱炎膀胱疼痛机制中的作用及作为治疗新靶点的价值

Painful bladder syndrome/interstitial cystitis (IC) is characterized by bladder pain due to unknown origin(s), whereas some complicate immunological and neurological reasons should be considered. Intercellular adhesion molecule 1 (ICAM-1) seems to interact with most IC pain-relate factors.Our previous study showed that reduction of ICAM-1 may play a role in the release of inlammation and pain. Based on our modified IC model in SD rats and new IC model in ICAM-1 deficiency mice, animal pain behavior, bladder pathology, tissue inflammatory factors and receptors through immunological (mast cell and prostaglandin E2) and neurological (purinergic signals and substance P/neurokinin 1 receptor) pathways are to be measured, aiming to identify the role of ICAM-1 in the mechanism of IC bladder pain.. Moreover, the accurate pain relief effect of ICAM-1 blockade will be evaluated in ICAM-1 deficiency mice compared with mast cell deficiency mice,along with the effect of combination blockade of ICAM-1 and mast cell.Therapeutic efficacy will be confirmed by evaluation of pain relief and ICAM-1 expression in IC patients receiving hyaluronic acid therapy. Our further purpose is to identify the exact value of ICAM-1 as a new therapeutic target for IC blader pain, as well as dual blockade of ICAM-1 with mast cell.

膀胱疼痛综合症/间质性膀胱炎(IC)以不明原因膀胱疼痛为特点，病因倾向于复杂的免疫和神经因素。细胞间粘附分子－1（ICAM-1）与多数IC疼痛因素关系密切，课题组研究发现降低ICAM-1可减轻IC炎症疼痛。基于自行改良SD大鼠IC模型和ICAM-1缺陷小鼠的新IC模型，研究疼痛过程中以及ICAM-1阻断在内的干预下，鼠疼痛行为学、组织病理、相关神经通路（嘌呤能受体、P物质/神经激肽受体）和免疫通路（前列腺素E2、肥大细胞）主要环节的变化，阐明ICAM-1在IC膀胱疼痛机制中的作用。通过ICAM-1缺陷小鼠和肥大细胞缺陷小鼠IC模型的比较、以及联合阻断ICAM-1和肥大细胞的研究，再经患者透明质酸膀胱灌注治疗验证，阐明ICAM-1作为IC疼痛治疗靶点的价值，探索ICAM-1和肥大细胞双重阻断的有效性。

间质性膀胱炎（IC）所致膀胱疼痛和膀胱挛缩严重困扰病人，病因不明，缺乏特异性治疗。.本课题在SD大鼠IC模型上使用抗ICAM-1抗体（AIA），研究膀胱炎症反应及相关炎症因子受体的改变。注射AIA的模型大鼠，膀胱炎症程度和肥大细胞浸润数显著降低，同时也降低了嘌呤能受体(P2X2/P2X3)、前列腺素E2受体( EP1/EP2)、TNF-α和NK1R。AIA作用优于塞来昔布和阿瑞匹坦，提示ICAM-1很可能是IC膀胱炎症的关键因素，有望成为新治疗靶点。.另外，通过两次免疫建立的自身免疫法小鼠IC模型（EAC），能很好模拟IC的排尿和膀胱疼痛症状，以及膀胱组织病理改变。在EAC小鼠注射AIA后，症状、膀胱炎症及炎性因子受体均有显著改善，且优于肥大细胞缺陷小鼠。该结果进一步证实ICAM-1的作用，且NK1R参与其调控。.总之，我们研究发现，神经激肽受体NK1R介导细胞间粘附分子－1（ICAM-1）参与的炎症免疫和神经病变在IC发病机制中起关键作用，SP－NK1R－ICAM-1通路为主的膀胱神经免疫调控很可能是IC疼痛和区域炎症免疫反应的关键环节，具有重要研究意义和治疗靶点价值。EAC小鼠模型为深入研究提供一个良好平台。