Persistence of Serotonergic Enhancement of Airway Response in a Model of Childhood Asthma

American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 01/2014; 51(1). DOI: 10.1165/rcmb.2013-0387OC
Source: PubMed


Rationale: Persistence of airway hyperresponsiveness and serotonergic enhancement of airway smooth muscle contraction induced by ozone plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to ozone plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for asthmatics. Objectives: To determine if previously documented airway hyperresponsiveness and serotonin-enhanced airway smooth muscle contraction in allergic monkeys exposed to ozone plus house dust mite allergen persist after prolonged recovery. Methods: Infant rhesus monkeys sensitized to house dust mite allergen were exposed to filtered air (n=6) or house dust mite allergen plus ozone (n=6) for 5 months. Monkeys were then housed in a filtered air environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested and airway smooth muscle contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin subtype receptor antagonists. Measurements and Main Results: Ozone plus house dust mite allergen exposed animals exhibited persistent airway hyperresponsiveness. Serotonin exacerbated the airway smooth muscle contraction in the exposure group, but not in the filtered air group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Conclusions: Airway hyperresponsiveness and serotonin-dependent exacerbation of cholinergic-mediated airway smooth muscle contraction induced by early-life exposure to ozone plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype.

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Available from: Brian D Moore, Jul 10, 2014
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    ABSTRACT: In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in lung parenchyma would be permanent following a long-term recovery in filtered (FA) housing. Forty-eight infant rhesus macaques (30days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O3) or HDMA/ozone (HDMA+O3) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes,interalveolar capillary density . After 30months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. . These alveoli also had higher capillary densities as compare with FA controls. These results indicate that early life exposure to HDMA alone or HDMA+O3 alters the development process in lung alveoli. Copyright © 2014. Published by Elsevier Inc.
    Toxicology and Applied Pharmacology 12/2014; 283(1). DOI:10.1016/j.taap.2014.12.006 · 3.71 Impact Factor