Paralysis of mucociliary clearance after cerebral ischemia by neurohumoral mechanisms
(Kummer / Meisel / Meisel)
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 in experimental and clinical studies 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. Using the mouse MCAO stroke 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 h 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.
In this project, we will
1. characterize the dynamics of changes in airway epithelial cell morphology, cellular composition of the epithelium and regeneration of mucociliary clearance after experimental stroke.
2. identify the mechanisms of stroke-induced cilia loss and epithelial changes.
3. elucidate the role of neurohumoral stress pathways in impaired mucociliary clearance after experimental stroke.
4. determine whether the mucociliary apparatus in stroke patients is affected in a similar manner as in mice after experimental stroke.