Secretion of pulmonary surfactant in the alveoli of the lungs is essential to maintain lung function. Stretching of alveoli during lung inflation is the main trigger for surfactant secretion. Yet, the molecular mechanisms how mechanical distension of alveoli results in surfactant secretion are still elusive. The alveolar epithelium consists of alveolar epithelial type I (ATI) and surfactant secreting type II (ATII) cells. ATI, but not ATII cells, express caveolae, small plasma membrane invaginations that can respond to plasma membrane stresses and serve mechanotransductive roles. Within this study, we investigated the role of caveolae as mechanosensors in the alveolus. We generated a human caveolin-1 knockout ATI cell (hAELVi^cav-/- ) using CRISPR/Cas9. Wildtype (hAELVi^wt ) and hAELVi^cav-/- cells grown on flexible membranes responded to increasing stretch amplitudes with rises in intracellular Ca²⁺ . The response was less frequent and started at higher stretch amplitudes in hAELVi^cav-/- cells. Stretch-induced Ca²⁺ -signals depended on Ca²⁺ -entry via piezo1 channels, localized within caveolae in hAELVi^wt and primary ATI cells. Ca²⁺ -entry via piezo1 activated pannexin-1 hemichannels resulting in ATP release from ATI cells. ATP release was reduced in hAELVi^cav-/- cells. In co-cultures resembling the alveolar epithelium, released ATP stimulated Ca²⁺ signals and surfactant secretion from neighboring ATII cells when co-cultured with hAELVi^wt but not hAELVi^cav-/- cells. In summary, we propose that caveolae in ATI cells are mechanosensors within alveoli regulating stretch-induced surfactant secretion from ATII cells.

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