Brain regulation of pulmonary dysfunction induced by stroke

Abstract

Ischaemic stroke, characterized with sterile brain tissue injury, can lead to acute pneumonia and pulmonary dysfunction, which are the primary causes of death in ischaemic stroke patients. The association of neural and molecular mechanisms between the infarcted brain area and the development of pneumonia and pulmonary dysfunction are not understood. We used whole-body plethysmography, the respiratory patterns test and arterial blood gas analysis to examine pulmonary function. In addition, Holter monitoring, electrophysiological recordings, chemogenetic manipulation, fibre photometry, ELISA, immunofluorescence, western blotting, reverse transcription-qPCR, haematoxylin and eosin staining, TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling) staining and viral-mediated manipulations were used to address our questions. Here, we observed significant pneumonia (immune cell infiltration and increased inflammatory cytokines) 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 ischaemic stroke. Mechanistically, ischaemic 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 neuron activity, via the α7 nicotinic acetylcholine receptor (α7nAChR), upregulates high mobility group box 1 (HMGB1) expression in the pulmonary parasympathetic ganglia neurons, which increases the expression of tumour necrosis factor-α and interleukin-1β in various immune cells via toll-like receptor 4 or the receptor for advanced glycation end products (RAGE). Meanwhile, the activation of circuit from DMVACh neurons to pulmonary parasympathetic ganglia neurons improved pneumonia and pulmonary dysfunction. These results dissect a novel neuroimmune framework that acute ischaemic stroke induces the apoptosis of DMVACh-innervating PVNCaMKII neurons, and subsequently promotes immune cell infiltration and increases in inflammatory cytokines via the α7nAChR-HMGB1 pathway in the pulmonary ganglion neurons, which leads to pulmonary dysfunction. These results provide a novel insight into the pathogenesis of pneumonia and pulmonary dysfunction after acute ischaemic stroke.

Keywords: HMGB1; apoptosis; ischaemic stroke; lung; neural circuit; parasympathetic nerve.