Transient receptor potential vanilloid 4 (TRPV4) channels mediate pulmonary surfactant protein A and D secretion.

Lung surfactant not only reduces surface tension at the air-liquid interface (ALI), but is also involved in pulmonary host defense. This important role in innate immunity of the respiratory tract is primarily mediated by surfactant proteins A and D (SP-A, SP-D), which are secreted from alveolar epithelial type 2 (AT2) cells and from tracheal and bronchial epithelial cells expressing transient receptor potential vanilloid 4 (TRPV4) channels. In a mouse model deficient in TRPV4 (TRPV4-/-), reduced levels of SP-A and SP-D were detected in the bronchoalveolar lavage fluid. Production of both proteins in TRPV4-/- AT2 cells was not different to wild-type control cells, but secretion of SP-A and -D was impaired both in TRPV4-deficient murine AT2 and murine tracheal epithelial cells cultured at the ALI. In a translational approach, we established a human ALI model and differentiated bronchial basal cells to a pseudostratified epithelium. Downregulation of Trpv4 mRNA expression by specific siRNAs also resulted in a reduction of secreted SP-A levels. Interestingly, differentiation of basal cells to ciliated cells, but not club cells, which secrete SP-A and SP-D, was decreased after downregulation of TRPV4. Our data highlight novel essential functions of TRPV4 channels in secretion of SP-A and SP-D, which are important not only for innate immunity, but also for lung diseases like asthma and idiopathic pulmonary fibrosis.