Hyperoxia and interferon-γ-induced injury in developing lungs occur via cyclooxygenase-2 and the endoplasmic reticulum stress-dependent pathway

We noted a marked increase in cyclooxygenase-2 (Cox2) and the activationof theendoplasmic reticulum(ER) stresspathway innewborn murinelungonexposure tohyperoxiaandIFN-γ.Wesoughttoevaluate Cox2-mediated ER stress pathway activation in hyperoxia-induced and IFN-γ-mediated injury in developing lungs.We applied in vivo genetic gain-of-function and genetic/chemical inhibition, aswell as in vitro lossof- function genetic strategies.Hyperoxia- induced and IFN-g-mediated impaired alveolarization was rescued by Cox2 inhibition, using celecoxib. The use of small interfering RNA against the ER stress pathway mediator, theC/EBPhomologousprotein(CHOP;alsoknownasgrowth arrest andDNAdamage-inducible gene 153/GADD153), alleviated cell death in alveolar epithelial cells aswell as in hyperoxia-induced andIFNγ- mediated murine models of bronchopulmonary dysplasia (BPD). In addition, CHOP siRNA also restored alveolarization in the in vivo models. Furthermore, as evidence of clinical relevance, we show increased concentrations of Cox2 and ER stress pathway mediators in human lungs with BPD. Cox2, via CHOP, may significantly contribute to the final common pathway of hyperoxia-induced and IFN-g-mediated injury in developing lungs and human BPD.