Lung surfactant reduces not only surface tension at the air liquid interface, 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, -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, reduced levels of SP-A and SP-D were detected in the bronchoalveolar lavage (BAL) 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 in murine tracheal epithelial cells (MTEC) cultured at the air liquid interface (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 -D, was decreased after down-regulation 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 (IPF).
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