Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice

Division of Intramural Research, NIH/NIEHS, Triangle Park, NC 27709, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 02/2007; 175(2):126-35. DOI: 10.1164/rccm.200509-1493OC
Source: PubMed


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.
To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice.
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.
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.
These data suggest that estrogen receptor-alpha is a critical regulator of airway hyperresponsiveness in mice.

Download full-text


Available from: Vickie R Walker, Oct 09, 2015
33 Reads
  • Source
    • "Additionally, female estrogen receptor-α-deficient mice are more sensitive to methacholine aerosol, either in the presence or the absence of allergic airway inflammation (Carey, et al. 2007). This hypercontractile phenotype in receptor-α-deficient mice is associated with decreased M 2 expression and function (Carey et al. 2007). Finally, low dose, but not high dose, of estrogens decreases airway responsiveness in ovariectomized rats in the absence of airway inflammation (Degano, et al. 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect airway smooth muscle contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of airway smooth muscle, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on airway smooth muscle or indirectly via the nervous system by tuning the level of cholinergic activation of airway smooth muscle. Indeed, mediators generated from a diversity of organs, including the adrenals, pancreas, adipose tissues, gonads, heart, intestines and stomach affect the contractility of airway smooth muscle. Together, these results suggest that, apart from a paracrine mode of regulation, airway smooth muscle is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of airway smooth muscle contractility is overlooked.
    Journal of Endocrinology 06/2014; 222(2). DOI:10.1530/JOE-14-0220 · 3.72 Impact Factor
  • Source
    • "Invasive analysis of lung function was performed using the Flexivent system (Scireq, Montreal, Quebec, Canada) as previously described [43], [44]. Breifly, mice were anesthetized with xylazine and pentobarbital sodium (50 mg/kg of body weight), cannulated with an 18G needle (for the delivery of methacholine) and artificially ventilated at 150 breaths/min with a tidal volume of 0.3 ml and a positive end expiratory pressure of 3 cm H2O. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human metapneumovirus (hMPV) is one of the main causes of acute respiratory tract infections in children, elderly and immunocompromised patients. The mammalian Toll-like receptors (TLR) were identified as critical regulators of innate immunity to a variety of microbes, including viruses. We have recently shown that hMPV-induced cytokine, chemokine and type I interferon secretion in dendritic cells occurs via TLR4, however, its role in hMPV-induced disease is unknown. In this study, wild-type(WT) and TLR4-deficient mice (TLR4(-/-)) were infected with hMPV and examined for clinical disease parameters, such as body weight loss and airway obstruction, viral clearance, lung inflammation, dendritic cell maturation, T-cell proliferation and antibody production. Our results demonstrate that absence of TLR4 in hMPV-infected mice significantly reduced the inflammatory response as well as disease severity, shown by reduced body weight loss and airway obstruction and hyperresponsiveness (AHR), compared to WT mice. Levels of cytokines and chemokines were also significantly lower in the TLR4(-/-) mice. Accordingly, recruitment of inflammatory cells in the BAL, lungs, as well as in lymph nodes, was significantly reduced in the TLR4(-/-) mice, however, viral replication and clearance, as well as T-cell proliferation and neutralizing antibody production, were not affected. Our findings indicate that TLR4 is important for the activation of the innate immune response to hMPV, however it does play a role in disease pathogenesis, as lack of TLR4 expression is associated with reduced clinical manifestations of hMPV disease, without affecting viral protection.
    PLoS ONE 10/2013; 8(10):e78849. DOI:10.1371/journal.pone.0078849 · 3.23 Impact Factor
  • Source
    • "However, gallamine treatment increased the responses to MCh in AIRmin animals indicating some activity of M2 receptor, but this activity was not sufficient to generate statistically significant data when compared to untreated group. In our study, we only used one dose of gallamine based on a previous report [28]. Taken together, these results indicate that the negative modulatory effect exerted by vagal M2 receptors was present in AIRmax mice but minimally in AIRmin animals. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh), which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic) and allergen-induced (extrinsic) airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax) or minimally (AIRmin) to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation.
    04/2013; 2013:805627. DOI:10.1155/2013/805627
Show more