title: Repeated β2-adrenergic receptor agonist therapy attenuates the response to rescue bronchodilation in a hyperoxic newborn mouse model.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Neonatology, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
authors: Thomas
authors: T
authors: Raffay
authors: Prabha
authors: P
authors: Kc
authors: James
authors: J
authors: Reynolds
authors: Juliann
authors: J
authors: Di Fiore
authors: Peter
authors: P
authors: MacFarlane
authors: Richard J
authors: RJ
authors: Martin
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000336:Aerosols; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001985:Bronchial Provocation Tests; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D000068759:Formoterol Fumarate; D018496:Hyperoxia / Q000150:complications* / Q000503:physiopathology; D064412:Levalbuterol / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D055370:Lung Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000336:Aerosols; D001993:Bronchodilator Agents; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D064412:Levalbuterol; D000068759:Formoterol Fumarate