Novel Neural Mechanisms underlying Lung-Heart Pathological Crosstalk

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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.