Stretch, Piezo channels, and store operated calcium entry in developing human airway smooth muscle.

backgroundContinuous positive airway pressure (CPAP) is a commonly used respiratory support strategy for premature infants in the NICU. While beneficial to overall lung development, static stretch from CPAP may negatively impact subsequent bronchial airway development: a topic not well-understood. Mechanosensitive Piezo (PZ) channels play critical roles in calcium regulation and beyond, including in airway cells. In airway smooth muscle, stromal interaction molecule 1 (STIM1) at the endoplasmic reticulum and plasma membrane Orai1 channels are important mediators of the store operated calcium entry (SOCE) microdomain, triggering downstream contractility and remodeling effects. We investigated the hypothesis that interplay between PZ and SOCE microdomain promotes intracellular calcium in human fetal airway smooth muscle cells (fASM) towards increasing contractility by stretch. METHODS AND

resultsProtein and calcium imaging studies of fASM in the presence of static stretch superimposed on rhythmic stretch show increased expression of Orai1 channels and caveolin-1 (but not STIM1) and nuclear translocation of β-catenin. Such stretch-induced changes are PZ-mediated as determined using PZ antagonists, which also blunt SOCE functionality.

conclusionOur findings suggest that with stretch, mechanosensitive PZ channels via SOCE contribute to CPAP-associated changes in airway structure and function. IMPACT: Developing airways are more compliant and sensitive to stretch from breathing and the pressure of CPAP or mechanical ventilation. The mechanisms by which stretch influences developing airways are not well-understood, but are highly relevant to appreciating the impact of iatrogenic interventions such as CPAP. Using developing human airway cells, we found that stretch activates mechanosensitive Piezo channels that trigger downstream signaling involving microdomains that increase cellular calcium, and β-catenin activation.