下丘脑SF1神经元通过交感神经调控肺神经气道相关巨噬细胞NF-κB信号通路在急性肺损伤中的作用研究

ALI/ARDS是临床常见危重症，严重威胁患者生命。预实验显示SF1神经元在ALI动物模型中异常活化；激活SF1神经元可在ALI模型中上调肺内NF-κB信号和血TNF-α水平，活化肺交感神经。这提示SF1神经元可能通过交感神经发挥神经免疫调节作用，并参与ALI的发生发展，有可能为治疗ALI/ARDS另辟蹊径。肺内神经气道相关巨噬细胞（NAMs）与交感神经关系密切，并高度表达免疫调节基因。本研究认为NAMs有可能是SF1神经元-交感神经-肺巨噬细胞调控通路的肺内靶细胞。为此拟进一步考察肺交感神经活性抑制状态下，正反两方面调控SF1神经元活性对ALI模型和交感神经的影响，证明SF1神经元对ALI和交感神经的作用，以及探索其可能作用的肺内巨噬细胞亚型。预期结果可能证明SF1-交感神经-NAMs神经免疫调控通路的存在及其在ALI中的调控作用，为ALI/ARDS的新机制和新靶点开发提供证据。

Clinically, ALI/ARDS is a common but devastatingly critical disease that seriously threatens the patients’ lives. Previous research shows that hypothalamic SF1 neurons are abnormally activated in the mice model of ALI, Precisely targeted activation of SF1 neurons through chemical genetic methods give rise to activation of lung sympathetic nerve as well as elevated inflammatory responses both in the lungs (NF-κB signaling) and in the peripheral blood (TNF-α) in the animal model of ALI. All these data indicate that SF1 neurons may exert their neuro-immunoregulatory functions through the sympathetic nerve and thus play a role in the pathogenesis of ALI, hence may provide a special but promising direction for overcoming ALI/ARDS. Pulmonary nerve airway associated macrophages (NAMs) are resided closely related to sympathetic nerves and can express high levels of immunoregulatory genes. We postulate that NAM may present as the key target effector cells participating the regulatory pathway of SF1 neuron-symphathetic nerve-lung macrophages. We designed the current study to further explore the impacts of SF1 activation or inhibition on ALI and the sympathetic nerve in case of sympathetic nerve deletion, so as to prove the role of SF1 on ALI and lung sympathetic fibers and the subtype effector cells of lung macrophages. The results may provide evidence to support the existence of SF1-symphathetic nerve-NAM neuroimmunoregulatory axis and its regulation on ALI, to provide evidences for elucidating new mechanisms and novel drug targets in ALI/ARDS.