基于NGF-TrkA正反馈通路探讨气道上皮细胞损伤修复-感觉神经纤维重塑在慢性咳嗽高敏发病机制中的作用研究

咳嗽高敏是难治性慢性咳嗽的病理生理基础，引起持续性咳嗽高敏的机制尚不清楚。申请者前期研究发现此类患者气道感觉神经纤维存在重塑，且其诱导痰中神经生长因子（nerve growth factor, NGF）水平升高，NGF可能来源于损伤修复的气道上皮细胞。既往研究提示NGF-TrkA正反馈通路可引起神经重塑。由此推测，气道上皮细胞损伤修复-感觉神经纤维重塑通过NGF-TrkA正反馈通路促进慢性咳嗽高敏。本项目将通过临床试验观察难治性慢性咳嗽患者气道上皮细胞NGF的合成量及NGF对咳嗽反射敏感性的增强效应；通过豚鼠咳嗽高敏模型观察TrkA受体拮抗剂对NGF引起的咳嗽敏感性增高和气道感觉神经重塑的抑制作用；并通过气道上皮细胞和神经细胞共培养模型阐明NGF-TrkA正反馈环路在慢性咳嗽高敏感性中的促进作用。项目的成功进行将为难治性慢性咳嗽的治疗提供新的靶点。

Cough hypersensitivity is the pathophysiology of refractory chronic cough, but its mechanism remains unknown. Our previous studies found that airway sensory neuroplasticity, which manifested as increased sensitivity and expression of cough receptors occurs in patients with refractory chronic cough. Elevated sputum nerve growth factor (NGF) probably produced by injured airway epithelial cells was also shown in these patients. Previous studies indicated that NGF-TrkA positive feedback loop can result in sensory neuroplasticity. Based on these findings, we speculate airway epithelial cell repair and sensory neuroplasticity contribute to chronic cough hypersensitivity via NGF-TrkA positive feedback loop. To prove our speculation, patients with chronic cough will be recruited to observe the NGF expression in airway epithelial cell and the potentiation of NGF to cough reflex sensitivity; cough hypersensitivity guinea pig model will be established to evaluate the inhibitory effect of TrkA antagonist on airway sensory neuroplasticity; besides, airway epithelial cell and neuron co-culture model will be established to clarify the attribution of NGF-TrkA positive feedback loop to persistent cough hypersensitivity. This study will help to provide novel therapeutic target for refractory chronic cough.