Dose-dependent effects of glucocorticoids on pulmonary vascular development in a murine model of hyperoxic lung injury

Abstract

BACKGROUND Exposure of neonatal mice to hyperoxia results in pulmonary vascular remodeling and aberrant phosphodiesterase-5 (PDE5) signaling. Although glucocorticoids are frequently utilized in the NICU, little is known about their effects on the developing pulmonary vasculature and on PDE5. We sought to determine the effects of hydrocortisone (HC) on pulmonary vascular development and on PDE5 in a neonatal mouse model of hyperoxic lung injury. METHODS C57BL/6 mice were placed in 21% O2 or 75% O2 within 24h of birth and received HC (1, 5, or 10 mg/kg subcutaneously every other day) or vehicle. At 14d, right ventricular hypertrophy (RVH), medial wall thickness (MWT), lung morphometry, and pulmonary artery (PA) PDE5 activity were assessed. PDE5 activity was measured in isolated pulmonary artery smooth muscle cells (PASMC) exposed to 21% or 95% O2 ± 100nM HC for 24h. RESULTS Hyperoxia resulted in alveolar simplification, RVH, increased MWT, and increased PA PDE5 activity. HC decreased hyperoxia-induced RVH and attenuated MWT. HC had dose-dependent effects on alveolar simplification. HC decreased hyperoxia-induced PDE5 activity in vivo and in vitro. CONCLUSIONS HC decreases hyperoxia-induced pulmonary vascular remodeling and attenuates PDE5 activity. These findings suggest that HC may protect against hyperoxic injury in the developing pulmonary vasculature.

Deconvolution of RNA-Seq Analysis of Hyperbaric Oxygen-Treated Mice Lungs Reveals Mesenchymal Cell Subtype Changes

“…Although HBO treatment promotes neovascularization [1], this effect seems to be tissue specific, as HBO exposure may reduce the blood vessel density in some cancer models [49,50]. Furthermore, both high and low oxygen concentrations have been reported to cause pulmonary vascular remodeling in neonatal infants [5,51]. We suggest that the reduction in the endothelial cell population might be an adaptive response to extra oxygen.…”

“…The lungs are the primary sites of oxygen toxicity, as a result of their direct exposure to the high partial pressure of oxygen during HBO treatment. Several conditions in pre-term and neonatal infants have been reported which are linked to hyperoxia, including hyperoxia-induced impairment of alveolarization, pulmonary inflammation, bronchopulmonary dysplasia complicated with pulmonary hypertension suggesting the developing lung is more sensitive to hyperoxia [2][3][4][5][6]. Conversely, the impact of hyperoxia on the adult lung appears to be relatively mild with current HBO therapies being reported to be clinically safe [7].…”

Early low-dose hydrocortisone: is the neurodevelopment affected?

“…In addition, fetal cortisol synthesis is immature such that the fetus makes minimal cortisol; therefore, many very low birthweight infants will have low blood cortisol values and may be functionally adrenally insufficient [2]. Last, animal studies demonstrate that postnatal steroids can have dose-dependent and variable effects on the developing lung, from inducing alveolarization arrest to attenuation of hyperoxia-induced pulmonary vascular remodeling [3, 4]. …”