Effects of Calcium Channel Blockade on Mammalian Lung Branching Morphogenesis

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Abstract
The bronchial tree is formed during the pseudo-glandular stage of lung development in a process termed lung branching morphogenesis. Coinciding with the period of lung branching morphogenesis is the appearance of spontaneous airway contractions, a phenomenon whose role in development remains unclear. In this study, an in vitro model of murine lung branching morphogenesis was used to examine the potential role of airway contractions in airway branching and lung growth. Spontaneous airway contractions of the proximal airways were observed in cultured murine lungs (obtained at 11 days of gestation) after 48 h in culture. Airway contractility was inhibited in a reversible manner by the voltage-dependent calcium channel blocker Nifedipine. Interestingly, long-term incubation of lung rudiments with Nifedipine not only prevented airway contraction, but also caused lung hypoplasia. The Nifedipine-treated hypoplastic lungs showed a normal branching pattern, suggesting that airway contractions and calcium channel function are not necessary for cleft formation directly. These observations suggest that calcium ion transport is necessary for development of airway contractions and for normal progression of lung growth.