Pathologic Wall Shear Stress in the Trachea Decreases Epithelial Differentiation and Increases Fibrosis

Mechanical ventilation is integral to the medical management of the critically ill. However, prolonged exposure to pathologic airflow during mechanical ventilation places patients at risk for airway injury. Here, we developed an innovative microsurgical mouse model to examine how changes in airflow affect cellular regeneration and repair in the tracheobronchial airway. We examined wall shear stress (WSS), a known consequence of airflow constriction, and evaluated clinical significance using Heliox, a helium-rich environment, which reduces pathologic airflow in human patients. We modulated airflow by altering airway geometry. Specifically, orthotopic airway transplants replaced a tracheal segment with either a bronchial scaffold (BrS) or a tracheal scaffold (TrS) (control) (n = 10/group). Post-surgery, mice were subjected to room air (1- or 2-weeks) or Heliox (1-week). Computational Fluid Dynamics models were used to quantify WSS. Epithelial and fibroblast cell number and phenotype, and collagen density were analyzed using histology. Statistical analysis was performed using 1-way ANOVA with multiple-comparison test. Using our novel microsurgical model, we reduced airway cross-sectional area by 0.54-fold and increased WSS by 71.40-fold. This increase in WSS was associated with squamous epithelial differentiation, increased fibroblast activation, and significant fibrosis. These phenotypic changes were rescued when mice were recovered in Heliox. Our findings suggest a mechanical mechanism in which airflow regulates epithelial differentiation, fibroblast activation, and fibrosis in the tracheobronchial airway. These studies support the development of therapeutic interventions that modulate intraluminal WSS and have the potential to accelerate airway regeneration.