激活迷走神经-α7 nAChR通路调控骨髓干(祖）细胞治疗急性肺损伤

Despite intensive care, fluid restriction, and protective mechanical ventilation, acute lung injury remains a mortality of 40%. Recent animal studies have demonstrated that administration of in vitro differentiated bone marrow mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) could reduce pulmonary inflammation and improve survival of acute lung injury. Both MSC and EPC express α7 nicotinic acetylcholine receptor (α7 nAChR). In vitro, activation of α7 nAChR in MSC and EPC renders protective effects on injured cells. Our previous studies have shown that activation of vagus nerve-α7 nAChR pathway could attenuate acid aspration or E. coli-induced acute lung injury. However, whether vagus nerve through α7 nAChR could mobilize bone marrow stem (progenitor) cells, thereby affect the outcome of acute lung injury is unclear. In this project, we will take molecular biological, immunological, neurophysiological and other advanced apporoaches to study (i) whether activation of vagus nerve-α7 nAChR pathway would mobilize α7 nAChR-expressing bone marrow stem (progenitor) cells to repair acute lung injury; how vagus nerve-α7 nAChR pathway would utilize AKT1, HIF-1α, and CXCR4 to regulate mobilization and migration of α7 nAChR-expressing bone marrow stem (progenitor) cells for attenuating acute lung injury. Targeting α7 nAChR-expressing bone marrow stem (progenitor) cells might provide us novel avenue to reduce severity of acute lung injury.

尽管采用重症监护、限制液体和保护性机械通气技术，急性肺损伤（ALI）患者死亡率仍高达40%。实验表明骨髓间充质干细胞（MSC）和内皮祖细胞（EPC）对ALI有保护作用。MSC和EPC均表达α7 nAChR。通过活化α7 nACh可以增加干细胞对损伤组织的修复作用。我们发现激活迷走神经和α7 nAChR可以减轻酸吸入或E. coli诱发的ALI。然而，尚不清楚激活迷走神经和α7 nAChR能否调控骨髓干（祖）细胞对ALI的修复作用。本项目我们将应用分子生物学、免疫学、神经生理学等先进手段来研究：（1）激活迷走神经-α7 nAChR通路调动α7 nAChR+骨髓干（祖）细胞对ALI的修复作用；（2）阐明迷走神经-α7 nAChR通路通过AKT1、HIF-1α和CXCR4等信号分子参与α7 nAChR+骨髓干（祖）细胞动员、迁移、和修复ALI的分子机制。研究成果将为ALI提供新的治疗靶点。

尽管采用重症监护、限制液体和保护性机械通气技术，急性肺损伤（ALI）患者死亡率仍高达40%。实验表明骨髓间充质干细胞（MSC）和内皮祖细胞（EPC）对ALI 有保护作用。MSC 和EPC 均表达α7 nAChR。通过活化α7 nAChR可以增加干细胞对损伤组织的修复作用。.我们应用分子生物学、免疫学、神经生理学等先进手段来研究了α7 nAChR 表达的骨髓干（祖）细胞在急性肺损伤中随病程变化的规律；明确了激活迷走神经和α7 nAChR 调动骨髓干（祖）细胞修复急性肺损伤的作用；明确了AKT1在迷走神经-α7 nAChR 通路对α7 nAChR+骨髓干（祖）细胞调动和参与急性肺损伤修复的作用。同时我们研究了肺副交感神经反射弧和脾脏对急性肺损伤的协调调控作用。.我们发现α7 nAChR特异性地表达在VEcadherin+Sca1+FLK1+的内皮祖细胞；急性肺损伤时，迷走神经切除导致肺内该类细胞减少，不利于损伤肺的修复；激活α7 nAChR可以在肺内增加该类细胞，促进急性肺损伤的修复。我们还发现了迷走神经和脾脏协同调控α7 nAChR+CD11b+炎症细胞由脾向肺移动，进而影响急性肺损伤的转归。.本项目深化了我们对骨髓、肺、脾干性和炎症细胞神经调控分子机制的认识，完善了迷走神经协同调控肺-脾间炎症细胞迁移影响急性肺损伤的分子机制。该成果将为新生学科-电生物医学（Electrical Biomedicine）对疾病的治疗提供理论基础。