Opposing regulation of human alveolar Type II cell differentiation by nitric oxide and hyperoxia

摘要

Clinical trials demonstrated decreasing rates of bronchopulmonary dysplasia in preterm infants with hypoxic respiratory failure treated with inhaled nitric oxide (iNO). However, the molecular and biochemical effects of iNO on developing human fetal lungs remain vastly unknown. Using a well-characterized model of human fetal alveolar type II cells, we assessed the effects of iNO and hyperoxia, independently and concurrently, on NO-cGMP signaling pathway and differentiation. Exposure to iNO increased cGMP levels by 40-fold after 3 days and by 8-fold after 5 days despite constant expression of phosphodiesterase-5 (PDE5). The levels of cGMP declined significantly upon exposure to iNO and hyperoxia at 3 and 5 days although expression of soluble guanylyl cyclase (sGC) was sustained. Surfactant proteins B and C (SP-B, SP-C) and Thyroid Transcription Factor-1 (TTF-1) mRNA levels increased in cells exposed to iNO in normoxia, but not upon exposure to iNO plus hyperoxia. Collectively these data indicate an increase in type II cell markers when undifferentiated lung epithelial cells are exposed to iNO in room air. However, hyperoxia overrides these potentially beneficial effects of iNO despite sustained expression of sGC.