The impact of mechanical ventilation on immature airway smooth muscle: Functional, structural, histological, and molecular correlates

Preterm infants exposed to mechanical ventilation often develop airway dysfunction and bronchopulmonary dysplasia. The mechanisms of mechanical ventilation-induced airway injury are currently unknown. This study correlates the age-related effects of mechanical ventilation on airway function with structural alterations at the tissue, cellular, ultrastructural, and molecular levels. Mechanically ventilated and nonventilated tracheal rings were obtained from premature and newborn lambs. In tissue baths, the passive and active length-tension relationships and dose-response characteristics of the tracheal rings were determined. Fixed tracheal rings were digested and the resulting isolated smooth muscle cells measured. Rings were analyzed by light and electron microscopy. Additionally, protein was extracted from the tracheal smooth muscle and myosin heavy chain isoforms were separated by SDS-polyacrylamide gel electrophoresis and analyzed by densitometry. Mechanical ventilation resulted in a significant decrease of both the slope of the passive length-stress relationship and of maximal force generation, with both effects being most pronounced in the newborn age group. These age-related functional alterations correlated with a decrease in smooth muscle cell length and a disruption of ultrastructural architecture, which were also most pronounced in the older groups. Furthermore, mechanical ventilation resulted in epithelial denudation at all ages. There were no acute statistically significant effects of mechanical ventilation on myosin heavy chain isoform expression. This study demonstrates age-related effects of mechanical ventilation on the passive and active characteristics of tracheal function and provides a structural analysis of potential mechanisms. The mechanisms behind these functional differences involve ultrastructural changes in cell length, tissue matrix, and disruption of epithelial integrity. These findings help elucidate the pathogenesis of ventilator-induced airway injury.