Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate.

In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium () to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen-challenged mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different in and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall, mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.