Modulation of Distinct Asthmatic Phenotypes in Mice by Dose-Dependent Inhalation of Microbial Products
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Citation: Whitehead GS, Thomas SY, Cook DN. Modulation of Distinct Asthmatic Phenotypes in Mice by Dose-Dependent Inhalation of Microbial Products. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1307280.
Received: 26 June 2013
Accepted: 25 October 2013
Advance Publication: 29 October 2013
Background: Human asthmatics display considerable heterogeneity with regard to Th2-associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood.
Objective: We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled LPS.
Methods: Ovalbumin was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation and airway hyperresponsiveness (AHR).
Results: Mice instilled with OVA together with very low doses (≤ 10-3 µg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10-1 µg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the latter animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells having high display of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS.
Conclusions: The nature and longevity of Th2, Th17 and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics.
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EHP is proud to announce its 2013 Paper of the Year is “450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy” [Environ Health Perspect 120(10):1425–1431 (2012); doi:10.1289/ehp.1205412]. The Paper of the Year award is given to the most highly cited Research Article, Commentary, or Review Article published in the preceding 12 months.
Congratulations to authors Bonnie R. Joubert, Siri E. Håberg, Roy M. Nilsen, Xuting Wang, Stein E. Vollset, Susan K. Murphy, Zhiqing Huang, Cathrine Hoyo, Øivind Midttun, Lea A. Cupul-Uicab, Per M. Ueland, Michael C. Wu, Wenche Nystad, Douglas A. Bell, Shyamal D. Peddada, and Stephanie J. London.
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