Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice

Am J Respir Crit Care Med. 2007 Jan 15;175(2):126-35. doi: 10.1164/rccm.200509-1493OC. Epub 2006 Nov 9.


Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.

Objectives: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice.

Methods: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.

Measurements and main results: Estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.

Conclusions: These data suggest that estrogen receptor-alpha is a critical regulator of airway hyperresponsiveness in mice.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Allergens / immunology
  • Animals
  • Bronchial Hyperreactivity / blood
  • Bronchial Hyperreactivity / etiology*
  • Bronchial Hyperreactivity / physiopathology
  • Cytokines / metabolism
  • Electrophysiology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / physiology*
  • Estrogens / blood
  • Female
  • Inflammation / immunology
  • Lung / drug effects
  • Lung / innervation
  • Lung / physiopathology*
  • Methacholine Chloride / pharmacology
  • Mice
  • Mice, Knockout
  • Ovalbumin / immunology
  • Peripheral Nerves / physiology
  • Plethysmography
  • Receptor, Muscarinic M2 / analysis
  • Receptor, Muscarinic M2 / metabolism*
  • Respiratory Hypersensitivity / etiology*
  • Respiratory Hypersensitivity / immunology
  • Respiratory Hypersensitivity / physiopathology
  • Serotonin / pharmacology
  • Trachea / drug effects
  • Trachea / innervation
  • Trachea / physiopathology


  • Allergens
  • Cytokines
  • Estrogen Receptor alpha
  • Estrogens
  • Receptor, Muscarinic M2
  • Methacholine Chloride
  • Serotonin
  • Ovalbumin
  • Acetylcholine