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: 10593064
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593064
• 关键词: Address; Afferent Neurons; 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; Communication; 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; Macrophage Activation; Measures; Mechanics; Mediating; Modeling; Molecular; Morbidity - disease rate; Motor; Myocardial Infarction; Myocardial dysfunction; Nerve; Nervous System; 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 Arrhythmia; Vertebral column; Western Blotting; cardiovascular risk factor; comorbidity; cytokine; design; heart function; hemodynamics; immune activation; in vivo; indium-bleomycin; innovation; interest; interstitial; lung injury; mortality; mouse model; nanomedicine; neural; neuroinflammation; neuromechanism; neuronal cell body; neuronal excitability; new therapeutic target; novel; patch clamp; pressure; prevent; receptor; 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率和死亡率的主要原因。几个