Mechanical stretch promotes sustained proliferation and inflammation in developing human airway smooth muscle

Preterm infants frequently require respiratory support, including continuous positive airway pressure (CPAP), that imposes mechanical stretch on highly compliant perinatal airways. How this excess stress impacts airway development and function is not completely understood. Using human fetal airway smooth muscle (fASM), a key cell type in airway contractility and remodeling, as a model, we investigated the effects of stretch, focusing on the role of mechanosensitive ion channels Piezo1 and Piezo2. We found that CPAP-like static stretch did not alter Piezo1 and Piezo2 protein expression per se and had a minimal effect on fASM cell proliferation or IL-6 production during the stretch period. However, CPAP-like stretch produces long-term effects in fASM, leading to increased cell proliferation and IL-6 production during the poststretch period, though interestingly, it does not enhance extracellular matrix deposition. The role of Piezo channels appears context-dependent in that the Piezo1 antagonist GsMTx4 reduced baseline proliferation in nonstretched cells but slightly increased proliferation in stretched cells. Piezo1 and Piezo2 inhibition did not alter IL-6 production. These results suggest that stretch induces a sustained increase in cell proliferation and inflammatory responses, which may contribute to long-term remodeling in former preterm infants initially exposed to CPAP.<b>NEW & NOTEWORTHY</b> Mechanical stretch associated with respiratory support can impair airway development and function in neonates, but the mechanisms are not fully understood. Using developing human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic continuous positive airway pressure, we found that stretch dysregulates long-term cell proliferation and inflammatory cytokine production, and mechanosensitive Piezo ion channels may play a role in the proliferation response.