BackgroundMechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury.MethodsExpression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively.ResultsTRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4.ConclusionThese studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.

Background: Mechanical forces and ErbB receptors are critical for fetal lung development. Results: Deletion of ErbB1 or down-regulation or ErbB4 prevented stretch-induced type II cell differentiation via ERK. Conclusion: Interactions between ErbB1 and ErbB4 are critical for stretch-induced type II cell differentiation. Significance: Learning how mechanical signal regulate fetal lung development is critical to develop strategies to accelerate lung maturation.

Background: Mechanical forces are critical for normal fetal lung development. Results: Force applied to ␣ 6 ␤ 1 integrin activates TACE and sheds HB-EGF and TGF-␣. Conclusion: Mechanical strain enhances binding of ␣6␤1 integrin to TACE to promote fetal type II cell differentiation. Significance: Learning how mechanical forces regulate fetal lung development is critical for the discovery of approaches to accelerate lung maturation.