Background: Continuous positive airway pressure (CPAP) is a primary mode of respiratory support for preterm infants. Animal studies have shown long-term detrimental effects on lung/airway development, particularly airway (AW) hyper-reactivity, as an unfortunate consequence of neonatal CPAP. Since the hyaluronan (HA) synthesizing enzyme hyaluronan synthase-3 (HAS3) is involved in various adult pulmonary disorders, the present study used a neonatal mouse model to investigate the role of HAS3 in CPAP-induced AW hyper-reactivity. Methods: Male and female neonatal mice were fitted with a custom-made mask for delivery of daily CPAP 3 h/day for 7 days. At postnatal day 21 (two weeks after CPAP ended), airway (AW) hyper-reactivity and HAS3 expression were assessed with and without in vitro HAS3 siRNA treatment. Results: MRIs of 3-day-old mice confirmed that CPAP increased lung volume with incrementing inflation pressures. CPAP increased AW reactivity in both male and female mice, which was associated with increased airway smooth muscle and epithelial HAS3 immunoreactivity. CPAP did not affect HA accumulation, but HAS3 siRNA reversed CPAP-induced AW hyper-reactivity and reduced HAS3 expression. Conclusions: These data in mice implicate a role for HAS3 in long-term effects of CPAP in the developing airway in the context of preterm birth and CPAP therapy.

Continuous infusion of prostaglandin E1 (PGE1) is used to maintain ductus arteriosus patency in infants with critical congenital heart disease, but it can also cause central apnea suggesting an effect on respiratory neural control. In this study, we investigated whether: 1) PGE1 inhibits the various phases of the acute hypoxic ventilatory response (HVR, an index of respiratory control dysfunction) and increases apnea incidence in neonatal rats; and 2) whether these changes would be reversible with caffeine pretreatment. Whole-body plethysmography was used to assess the HVR and apnea incidence in neonatal rats 2 hours following a single bolus intraperitoneal injection of PGE1 with and without prior caffeine treatment. Untreated rats exhibited a biphasic HVR characterized by an initial increase in minute ventilation followed by a ventilatory decline of the late phase (~5th minute) of the HVR. PGE1 had a dose-dependent effect on the HVR. Contrary to our hypothesis, the lowest dose (1µg/kg) of PGE1 prevented the ventilatory decline of the late phase of the HVR. However, PGE1 tended to increase post-sigh apnea incidence and the coefficient of variability (CV) of breathing frequency suggesting increased respiratory instability. PGE1 also decreased brainstem microglia mRNA and increased nNOS and PDGFβ gene expression. Caffeine pretreatment prevented these effects of PGE1, and the adenosine A2a receptor inhibitor MSX-3 had similar preventative effects. Prostaglandin may have deleterious effects on brainstem respiratory control regions, possibly involving a microglial- and adenosinergic-dependent mechanism. Caffeine therapy might