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Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-–deficient Mice

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health; Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Departments of Medicine and Physiology, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Darryl C. Zeldin, M.D., NIH/NIEHS, 111 T.W. Alexander Drive, Building 101, Room D236 Research Triangle Park, NC 27709. E-mail: zeldin{at}niehs.nih.gov

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- 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- also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.

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

Key Words: lung function • asthma • hyperreactivity • M2 muscarinic receptor • estrogen receptor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The effect of estrogens in the lung is highly controversial and the results of published studies are contradictory. What This Study Adds to the Field This study suggests that estrogen receptor- is involved in airway hyperresponsiveness.

 

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