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1.  Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice 
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-α 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-α also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.
Conclusions: These data suggest that estrogen receptor-α is a critical regulator of airway hyperresponsiveness in mice.
doi:10.1164/rccm.200509-1493OC
PMCID: PMC1899278  PMID: 17095746
lung function; asthma; hyperreactivity; M2 muscarinic receptor; estrogen receptor
2.  Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice 
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-α 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-α also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.
Conclusions
These data suggest that estrogen receptor-α is a critical regulator of airway hyperresponsiveness in mice.
doi:10.1164/rccm.200509-1493OC
PMCID: PMC1899278  PMID: 17095746
lung function; asthma; hyperreactivity; M2 muscarinic receptor; estrogen receptor
3.  Cyclooxygenase-2 Regulates Th17 Cell Differentiation during Allergic Lung Inflammation 
Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.
Objectives: To determine the role of COX metabolites in regulating Th17 cell differentiation and function during allergic lung inflammation.
Methods: COX-1−/−, COX-2−/−, and wild-type mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th17 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time polymerase chain reaction, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown.
Measurements and Main Results: Th17 cell differentiation in lung, lymph nodes, and bronchoalveolar lavage fluid was significantly lower in COX-2−/− mice after ovalbumin sensitization and exposure in vivo. In vitro studies revealed significantly impaired Th17 cell differentiation of COX-2−/− naive CD4+ T cells with decreased Stat3 phosphorylation and RORγt expression. Synthetic PGF2α and PGI2 enhanced Th17 cell differentiation of COX-2−/− CD4+ T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF2α receptor and PGI2 receptor siRNA knockdown significantly decreased Th17 cell differentiation in vitro. Administration of synthetic PGs restored accumulation of Th17 cells in lungs of allergic COX-2−/− mice in vivo.
Conclusions: COX-2 is a critical regulator of Th17 cell differentiation during allergic lung inflammation via autocrine signaling of PGI2 and PGF2α through their respective cell surface receptors.
doi:10.1164/rccm.201010-1637OC
PMCID: PMC3172888  PMID: 21474648
Th17 cell; COX-2; asthma; prostaglandins; IL-17

Results 1-3 (3)