Brain regulation of pulmonary dysfunction induced by stroke

Abstract Ischemic stroke, characterized with sterile brain tissue injury, can lead to an acute pneumonia and pulmonary dysfunction, which are the primary causes of death in ischemic stroke patients. The neural and molecular mechanisms association between the infarcted brain area and the development of pneumonia and pulmonary dysfunction are not understood. We used the whole-body plethysmography, respiratory patterns test and arterial blood gas analysis to examine pulmonary function. In addition, holter monitoring, electrophysiological recordings, chemogenetic manipulation, fiber photometry, ELISA, immunofluorescence, Western blotting, RT-qPCR, HE staining, TUNEL staining and viral-mediated manipulations were used to address our questions. Here, we observed significant pneumonia (immune cells infiltration and inflammatory cytokines increases) and pulmonary dysfunction in middle cerebral artery occlusion rats. A decrease in parasympathetic nerve function and activity was observed in clinical patients and rodent models with acute ischemic stroke. Mechanistically, ischemic stroke leads to the apoptosis of glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVNCaMKII) that innervate acetylcholine neurons in the dorsal motor nucleus of the vagus (DMVACh), and subsequently decreases the activity of DMVACh neurons. The reduced DMVACh neurons activity, via α7 nicotinic acetylcholine receptor (α7nAChR), upregulates high mobility group box 1 (HMGB1) expression in the pulmonary parasympathetic ganglia neurons, which increases the expression of tumor necrosis factor-alpha and interleukin-1beta in various immune cells via the Toll-like receptor 4 (TLR4) or receptor for advanced glycation end products (RAGE). Meanwhile, the activation of circuit from DMVACh neurons to pulmonary parasympathetic ganglia neurons improved the pneumonia and pulmonary dysfunction. These results dissect a novel neuroimmune framework that acute ischemic stroke induces the apoptosis of DMVACh-innervating PVNCaMKII neurons, and subsequently promotes the immune cells infiltration and inflammatory cytokines increases by acting on the α7nAChR-HMGB1 pathway in the pulmonary ganglion neurons, which leads to pulmonary dysfunction. These provided a novel insight on the pathogenesis of pneumonia and pulmonary dysfunction after acute ischemic stroke.