Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice.
BACKGROUND
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.


OBJECTIVE
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.


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.
Carey
Michelle A
MA
Division of Intramural Research, NIH/NIEHS, Triangle Park, NC 27709, USA.
Card
Jeffrey W
JW
Bradbury
J Alyce
JA
Moorman
Michael P
MP
Haykal-Coates
Najwa
N
Gavett
Stephen H
SH
Graves
Joan P
JP
Walker
Vickie R
VR
Flake
Gordon P
GP
Voltz
James W
JW
Zhu
Daling
D
Jacobs
Elizabeth R
ER
Dakhama
Azzeddine
A
Larsen
Gary L
GL
Loader
Joan E
JE
Gelfand
Erwin W
EW
Germolec
Dori R
DR
Korach
Kenneth S
KS
Zeldin
Darryl C
DC
D000109:Acetylcholine / Q000378:metabolism; D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004594:Electrophysiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D004967:Estrogens / Q000097:blood; D005260:Female; D007249:Inflammation / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010525:Peripheral Nerves / Q000502:physiology; D010991:Plethysmography; D043585:Receptor, Muscarinic M2 / Q000032:analysis / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D012701:Serotonin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology
D000485:Allergens; D016207:Cytokines; D047628:Estrogen Receptor alpha; D004967:Estrogens; D043585:Receptor, Muscarinic M2; D016210:Methacholine Chloride; D012701:Serotonin; D010047:Ovalbumin; D000109:Acetylcholine