Paralysis of mucociliary clearance after cerebral ischemia by neurohumoral mechanisms

• Applicants: Professor Dr. Wolfgang Kummer; Professor Dr. Andreas Meisel; Dr. Christian Alexander Meisel
• Subject Area: Pneumology, Thoracic Surgery ; Experimental Models for the Understanding of Nervous System Diseases ; Clinical Infectiology and Tropical Medicine ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467201555

Pneumonia is a highly relevant complication and leading cause of death in patients after acute CNS injury such as ischemic stroke. We and others have previously demonstrated that temporary impairment of peripheral and pulmonary immune responses due to overactivation of neurohumoral stress pathways, besides other factors such as dysphagia, contributes to the high incidence of pneumonia in these patients. Importantly, our experimental mouse model of focal cerebral ischemia was highly predictive for stroke-induced immunodepression in patients. Using this model, we observed a striking alteration of the mucociliary clearance characterized by a reduction of ciliated cells and an increase in secretory cells of the trachea within less than 24 hours after stroke. These changes in cellular morphology and composition of the respiratory epithelium were associated with disturbed cilia motility and a strongly reduced cilia-driven particle transport on tracheal explants from stroke animals. Our data indicate a rapid stroke-induced impairment of the mucociliary escalator, the primary defence mechanism of the tracheo-bronchial tree against inhaled particles and pathogens, suggesting a novel pathogenic mechanism for the increased risk of respiratory infections after acute CNS injury. The present project aims to characterize in detail the dynamics of changes in airway epithelial cell morphology and composition after stroke over time and determine whether and when cellular and functional regeneration of the mucociliary clearance occurs. We will further investigate the cellular mechanisms of stroke-induced epithelial changes including increased autophagy or cell apoptosis as well as alterations in ciliogenesis, cell differentiation and proliferation. Moreover, we will investigate the mediators of impaired mucociliary clearance after stroke, particularly the role of neurohumoral stress pathways. Finally, we will address whether stroke-induced changes in cellular composition and function of the mucociliary escalator also occur in stroke patients and correlate these findings with clinical data such as stroke severity, dysphagia, activation of the autonomic nervous system, immune status and the occurrence of pulmonary infections. A better understanding of the mechanisms of impaired mucociliary clearance after stroke may have significant impact on treatment not only of patients with acute CNS injury but also of other critically ill patients.

• DFG Programme: Research Grants