迷走-神经上皮小体系统调控肺纤维化的作用机制

Pulmonary fibrosis (PF), especially idiopathic PF is a devastating and fatal disease with increasing prevalence rate. Despite extensive research efforts, our understanding of underlying disease mechanisms is limited and currently there is no effective treatment for IPF. Therefore, identifying the mechanisms that promote this disease is greatly needed to develop novel therapeutics. Increasing evidence indicates that the neuroimmune interaction is closely related to progression of PF. Our preliminary studies demonstrate that vagotomy attenuated bleomycin induced PF in mice and the vagal sensor-neuroepithelial body (NEB) count increased in the lung following bleomycin challenge. Thus, we hypothesize that Vagal-NEB System may detect changes of microenvironment during lung injury and produce bioactive substances to activate macrophage to M2 phenotype and then promote PF. To test this hypothesis, histological, cytological and molecular biological techniques will be applied to address three specific aims : 1. vagotomy or inhibitor of ACh receptor may promote PF; 2. fibrogenic molecules (TGF-β and IL-4) improve bioactivity of NEB; 3. neuroepithelial cells promote proliferation of fibroblasts. Its product-bioactive substances (GRP, CGRP, 5-HT) promote M2 polarization and then PF. This project will determine stimulation of the vagal-NEB system promotes PF, in vitro and in vivo. Successful completion of these studies will help establish a novel neural mechanism in the pathogenesis of PF. This could yield new approaches to improve or limit chronic fibrotic lung disease, as well as open up a new research field in pathogenesis and treatment of pulmonary diseases in terms of neuroimmune interaction.

特发性肺纤维化发病机制不明，致死率高，至今缺乏有效疗法。因此，探明肺纤维化的病理机制是寻找有效治疗方法的首要问题。众多研究表明神经内分泌系统可影响肺纤维化。我们发现切除迷走神经可减轻博来霉素诱发的肺纤维化；在病变发展过程中，迷走神经感受器-神经上皮小体（NEB）明显增生。由此，我们假设：迷走神经-神经上皮小体系统（VNS）可以感受损伤引起的微环境变化并释放生物活性物质激活巨噬细胞向M2型极化而促进肺纤维化。我们将应用组织学、分子生物学等实验技术验证：1.切除或者阻断迷走神经系统可改善肺纤维化；2.促纤维化因子TGF-β和IL-4可增强NEB的生物活性；3.神经上皮细胞可增强成纤维细胞增殖，它释放的GRP、CGRP和5-HT可增加M2型巨噬细胞并促进肺纤维化。该项目在整体和离体两个方面，奠定VNS的神经免疫机制在肺纤维化过程中的重要性，为改善或限制肺纤维化提供理论基础乃至新的治疗靶点。

肺纤维化（Pulmonary Fibrosis, PF）由弥漫性肺损伤所致。特发性肺纤维化发病机制不明，致死率高，至今缺乏有效疗法。近来，随着空气污染的加重，肺纤维化的发病率明显增加。因此，探明肺纤维化的潜在机制以便寻找有效治疗方法是迫切需要解决的问题。越来越多的证据表明神经内分泌系统参与调节免疫细胞反应和应答，激活迷走神经（Vagus Nerve）- 神经上皮小体（Neuroepithelial body, NEB）系统（VNS）可能促进肺纤维化的形成，而抑制VNS 可减轻PF。如能证实VNS 参与肺纤维化的发病机制，将有助于寻找新的治疗靶点。在该研究中，我们应用单侧迷走神经切除术观察博来霉素诱导的肺纤维化程度，来确定迷走神经的作用；2. 观察肺纤维化发展过程中NEB 的数量和大小变化，以确定在肺纤维化过程中，微环境变化对NEB 激活作用；3. 通过观察注射生物活性物质对肺纤维化的促进作用，神经上皮细胞及生物活性物质对巨噬细胞向M2 型极化，对成纤维细胞增殖转化的影响，在整体和离体两个方面，确定激活VNS 的促纤维化作用。我们研究结果提示：1. 去迷走神经支配改善博来霉素诱导的肺纤维化；2. 去迷走神经支配抑制了博来霉素诱导的促纤维化因子在肺脏的高表达；3. 去迷走神经支配抑制了博来霉素诱导的成纤维母细胞在肺脏的浸润；4. 去迷走神经支配抑制了博来霉素诱导的肺泡M2型巨噬细胞的浸润；5. 在博来霉素诱导的肺纤维化模型中观察到，肺纤维化后神经上皮小体数量和面积均增加；6. NEB生物活性物质5-HT可促进巨噬细胞向M2型转化。我们的研究为探讨迷走神经在神经免疫交互作用中参与肺部病理变化的机制提供重要证据，从而能加深我们对神经系统参与疾病的认识，特别是对肺纤维化发病机理和治疗注入新元素。