Novel Neural Mechanisms underlying Lung-Heart Pathological Crosstalk

肺心病理串扰背后的新神经机制

• 批准号: 10372944
• 负责人: Hanjun Wang
• 金额: $ 53.9万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372944
• 关键词: Address; Anatomy; Animal Experiments; Arrhythmia; Atrial Fibrillation; Attention; Autonomic Dysfunction; Autonomic Pathways; Autonomic ganglion; Autonomic nervous system; Bleomycin; Cardiac; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cells; Chest; Chronic; Chronic Obstructive Pulmonary Disease; Coculture Techniques; Congestive Heart Failure; Conscious; Critical Care; Data; Destinations; Disease; Efferent Neurons; Electrocardiogram; Excision; Exhibits; Filtration; Functional disorder; Ganglia; Goals; Heart; Heart Diseases; Heart Injuries; Immunofluorescence Immunologic; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Interstitial Pneumonia; Knockout Mice; Lung; Lung diseases; Macrophage Activation; Measures; Mechanics; Mediating; Modeling; Molecular; Morbidity - disease rate; Motor; Myocardial Infarction; Myocardial dysfunction; Nerve; Nervous system structure; Neural Pathways; Neurons; Operative Surgical Procedures; Organ; Pathologic; Patients; Peripheral; Peripheral Nervous System; Pulmonary Heart Disease; Rattus; Reflex action; Regulation; Respiration Disorders; Role; Sensory; Sensory Ganglia; Spinal; Spinal Ganglia; Structure of stellate ganglion; Sympathetic Ganglia; System; TNF gene; TNFRSF1A gene; Techniques; Telemetry; Testing; Therapeutic Intervention; Time; Ventricular; Western Blotting; cardiovascular risk factor; comorbidity; cytokine; design; heart function; hemodynamics; immune activation; in vivo; indium-bleomycin; innovation; interest; interstitial; lung injury; macrophage; mortality; mouse model; nanomedicine; neuroinflammation; neuromechanism; neuronal cell body; neuronal excitability; new therapeutic target; novel; patch clamp; pressure; prevent; receptor; relating to nervous system; retrograde transport; spinal nerve posterior root; spine bone structure; therapy development; transcriptome sequencing; uptake

Pulmonary and cardiovascular diseases are leading causes of morbidity and mortality worldwide. Several pulmonary diseases are associated with cardiovascular complications, and vice versa. Therefore, an understanding of cardio-pulmonary interaction and the effects of disease and therapeutic interventions on cardio-pulmonary status is central to the management of patients with cardiopulmonary diseases. Over the past several decades, the interest in the cardiopulmonary critical care field has been largely focused on the mechanical interaction between the two organs. However, little attention has been given to a potential cardiopulmonary neural interaction via their shared autonomic ganglia. Considering the fact that the lungs and heart anatomically share common spinal afferents (i.e. T1-T4 dorsal root ganglia (DRG)) and efferent (i.e. stellate and T2-T4 sympathetic chains) nervous systems, here we hypothesize that damage to one organ (either heart or lung) will trigger a neuro-inflammatory cascade that includes macrophage activation in autonomic ganglia common to both organs. This results in alterations in both afferent and efferent sensitivities in both organs. To test this hypothesis, we will determine 1) if cardiac injury such as myocardial infarction (MI) chronically causes macrophage activation in T1-T4 DRGs and stellate ganglia, thus increasing both sympathetic afferent and efferent sensitivity to and from the heart and lungs; 2) if bleomycin-induced lung injury also causes macrophage activation in both T1-T4 DRGs and stellate ganglia, resulting in increased cardiac afferent and efferent sensitivity and cardiac arrhythmias. We will use highly integrative techniques including molecular (western blot, immunofluorescence and RNA-seq analysis), cellular (patch clamp) and whole animal experiments (measuring cardiopulmonary afferent reflexes, chronic conscious ECG telemetry recording and pressure-volume loop analysis of cardiac function) to test these hypotheses. The most exciting concept created by this proposal is that the heart and lung can reciprocally interact to sensitize their afferent and efferent autonomic pathways through macrophage activation at the level of their shared autonomic ganglia. To the best of our knowledge, this is a completely new mechanism, which has not been recognized before. The long-term impact of this study is the identification of macrophage infiltration into the peripheral nervous system as a new therapeutic target to treat cardiac and pulmonary diseases.

肺部和心血管疾病是全世界发病和死亡的主要原因。一些 肺部疾病与心血管并发症相关，反之亦然。因此，一个 了解心肺相互作用以及疾病和治疗干预措施的影响 心肺状态对于心肺疾病患者的治疗至关重要。过去的事 几十年来，人们对心肺重症监护领域的兴趣主要集中在 两个器官之间的机械相互作用。然而，人们很少关注潜在的 通过共享的自主神经节进行心肺神经相互作用。考虑到肺和 心脏在解剖学上共享共同的脊髓传入神经（即 T1-T4 背根神经节 (DRG)）和传出神经（即 星状和T2-T4交感链）神经系统，这里我们假设对一个器官的损害 （心脏或肺）将引发神经炎症级联反应，其中包括巨噬细胞激活 两个器官共有的自主神经节。这导致传入和传出敏感性的改变 两个器官。为了检验这一假设，我们将确定 1) 是否存在心脏损伤，例如心肌梗塞 (MI) 长期引起 T1-T4 DRG 和星状神经节中的巨噬细胞激活，从而增加 交感神经传入和传出心脏和肺的敏感性； 2) 如果博来霉素诱导肺 损伤还会导致 T1-T4 DRG 和星状神经节中的巨噬细胞激活，从而导致 心脏传入和传出敏感性和心律失常。我们将使用高度集成的技术 包括分子（蛋白质印迹、免疫荧光和 RNA-seq 分析）、细胞（膜片钳）和 整体动物实验（测量心肺传入反射、慢性意识心电图遥测 心功能的记录和压力-容量环分析）来检验这些假设。最激动人心的 该提案提出的概念是，心脏和肺可以相互作用，使它们的传入和肺变得敏感。 通过共享自主神经节水平的巨噬细胞激活传出自主神经通路。到 据我们所知，这是一种全新的机制，以前从未被认识到。 这项研究的长期影响是确定巨噬细胞浸润到周围神经 系统作为治疗心肺疾病的新靶点。