Repeated � 2 -Adrenergic Receptor Agonist Therapy Attenuates the Response to Rescue Bronchodilation in a Hyperoxic Newborn Mouse Model

Preterm infants with neonatal lung injury are prone to wheezing and are often treated with β2-adrenergic receptor (β-AR) agonists although the benefits of β-AR agonists may be lost with chronic use. To investigate if repeated β-AR agonist exposure downregulates β-ARs in the immature lung resulting in a decreased response to bronchodilator rescue and whether hyperoxic exposure aggravates this response. Newborn mice were raised for 21 days in 60 or 21% oxygen and received daily aerosols of formoterol or saline. Respiratory system resistance (Rrs) and compliance (Crs) were measured in response to methacholine challenge and rescue bronchodilation with levalbuterol. Western blot analysis quantified the relative amount of lung β-ARs. Hyperoxia increased the airway reactivity to methacholine. Animals raised in hyperoxia that received daily formoterol were most sensitive to methacholine and exhibited a blunted response to levalbuterol bronchodilation. Hyperoxia-exposed animals receiving daily formoterol versus saline showed a significant decrease in the relative amount of lung β-ARs. In this hyperoxia-exposed neonatal mouse model, repeated β-AR agonist treatments increased the airway reactivity and attenuated the response to a rescue bronchodilator. The blunted bronchodilator response could be explained by a reduced quantity of lung β-ARs. Our findings may account for the time-dependent decrease in the therapeutic benefit of β-AR agonists in preterm infants with neonatal lung injury, which may have clinical consequences for patients already prone to airway hyperreactivity.