AQP5调控免疫源性及神经源性CGRP比例失调引发肺纤维化的机制研究

Pulmonary fibrosis is the typical pathological manifestation of interstitial lung disease (ILD). The accelerated apoptosis of alveolar epithelial cells (AEC) could induce irreversible pulmonary fibrosis. Our previous study has found that the high frequency mutation of aquaporin 5 (AQP5) which could downregulate the expression of AQP5 so as to cause the excessive apoptosis of AEC in ILD. We further found that AQP5 could regulate the expression of immunogenic and neurogenic calcitonin gene-related peptide (CGRP). However, the specific mechanism is still unknown. So we hypothesized that it is a key role of abnormal expression of AQP5 gene in regulating the maladjustment of the immune source and nerve source CGRP leading to pulmonary fibrosis. A series of studies will be carried out based on this hypothesis through the following three aspects: 1) To investigate the dose effect relationship between AQP5 and CGRP in patients with ILD. 2) To verify the relationship between AQP5 and CGRP and the effect of abnormal expression of AQP5 on cell cycle in alveolar epithelial cells, using lentivirus mediated siRNA transfected the human alveolar epithelial cells HPAEpiC to silence AQP5 gene expression; 3) To verify whether AQP5 could regulate the process of apoptosis on alveolar epithelial cells leading to pulmonary fibrosis through the ras-related C3 botulinum toxin substrate 1 (RAC1)-CGRP pathway, the model of CGRP gene knock-out rats will be used to promote the development of related research. As it is a key role of abnormal expression of AQP5 gene in regulating the maladjustment of the immune source and nerve source CGRP, which caused the excessive apoptosis of AEC leading to pulmonary fibrosis, this study would be a new exploration for the triggering mechanism with ILD.

间质性肺疾病（ILD）典型病理表现为肺纤维化。肺泡上皮细胞（AEC）加速凋亡可诱发不可逆的肺纤维化。我们前期发现ILD中水通道蛋白5（AQP5）高频突变、进而引发AQP5表达下调导致AEC过度凋亡，深入研究发现AQP5可调节免疫源性和神经源性降钙素基因相关肽（CGRP）表达，但具体机制未明。我们推测“AQP5调控免疫源性及神经源性CGRP比例失调引发肺纤维化”，为验证假说将通过1）检测患者AQP5与CGRP表达的量效关系；2）利用慢病毒介导的siRNA转染人肺泡上皮细胞株HPAEpiC沉默AQP5基因，验证AQP5与CGRP的表达关系及对AEC细胞周期的影响；3）利用CGRP敲除鼠探讨AQP5是否通过Ras相关的C3肉毒素底物1（RAC1）-CGRP通路调控AEC凋亡致肺纤维化。本研究将从AQP5调控免疫源性和神经源性CGRP比例失调促进AEC凋亡致肺纤维化的新视点探索ILD的触发机制。