title: Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products.
abstract: BACKGROUND
  Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2-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 lipopolysaccharide (LPS).
  
  
  METHODS
  Ovalbumin (OVA) 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 10⁻¹ μg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels 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.
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Whitehead
authors.forename: Seddon Y
authors.initials: SY
authors.lastname: Thomas
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D010047:Ovalbumin