• Arul Vadivel, Tim van Haaften, Rajesh S Alphonse, Gloria-Juliana Rey-Parra, Lavinia Ionescu, Al Haromy, Farah Eaton, Evangelos Michelakis, and Bernard Thébaud.
• Department of Pediatrics, School of Human Development, Women and Children’s Health Research Institute, Edmonton, Canada.
• Am. J. Respir. Crit. Care Med. 2012 Mar 1; 185 (5): 564-74.

RationaleLung diseases characterized by alveolar damage currently lack efficient treatments. The mechanisms contributing to normal and impaired alveolar growth and repair are incompletely understood. Axonal guidance cues (AGC) are molecules that guide the outgrowth of axons to their targets. Among these AGCs, members of the Ephrin family also promote angiogenesis, cell migration, and organogenesis outside the nervous system. The role of Ephrins during alveolar growth and repair is unknown.ObjectivesWe hypothesized that EphrinB2 promotes alveolar development and repair.MethodsWe used in vitro and in vivo manipulation of EphrinB2 signaling to assess the role of this AGC during normal and impaired lung development.Measurements And Main ResultsIn vivo EphrinB2 knockdown using intranasal siRNA during the postnatal stage of alveolar development in rats arrested alveolar and vascular growth. In a model of O(2)-induced arrested alveolar growth in newborn rats, air space enlargement, loss of lung capillaries, and pulmonary hypertension were associated with decreased lung EphrinB2 and receptor EphB4 expression. In vitro, EphrinB2 preserved alveolar epithelial cell viability in O(2), decreased O(2)-induced alveolar epithelial cell apoptosis, and accelerated alveolar epithelial cell wound healing, maintained lung microvascular endothelial cell viability, and proliferation and vascular network formation. In vivo, treatment with intranasal EphrinB2 decreased alveolar epithelial and endothelial cell apoptosis, preserved alveolar and vascular growth in hyperoxic rats, and attenuated pulmonary hypertension.ConclusionThe AGC EphrinB2 may be a new therapeutic target for lung repair and pulmonary hypertension.

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