title: Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation.
abstract: BACKGROUND
  Asthma is a respiratory tract disorder characterized by airway hyper-reactivity and chronic inflammation. Allergic asthma is associated with the production of allergen-specific IgE and expansion of allergen-specific T-cell populations. Progression of allergic inflammation is driven by T-helper type 2 (Th2) mediators and is associated with alterations in the levels of lipid mediators.
  
  
  OBJECTIVE
  Responses of the respiratory system to birch allergen provocation in allergic asthmatics were investigated. Eicosanoids and other oxylipins were quantified in the bronchoalveolar lumen to provide a measure of shifts in lipid mediators associated with allergen challenge in allergic asthmatics.
  
  
  METHODS
  Eighty-seven lipid mediators representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS following off-line extraction of bronchoalveolar lavage fluid (BALF). Multivariate statistics using OPLS were employed to interrogate acquired oxylipin data in combination with immunological markers.
  
  
  RESULTS
  Thirty-two oxylipins were quantified, with baseline asthmatics possessing a different oxylipin profile relative to healthy individuals that became more distinct following allergen provocation. The most prominent differences included 15-LOX-derived ω-3 and ω-6 oxylipins. Shared-and-Unique-Structures (SUS)-plot modeling showed a correlation (R(2) = 0.7) between OPLS models for baseline asthmatics (R(2)Y[cum] = 0.87, Q(2)[cum] = 0.51) and allergen-provoked asthmatics (R(2)Y[cum] = 0.95, Q(2)[cum] = 0.73), with the majority of quantified lipid mediators and cytokines contributing equally to both groups. Unique structures for allergen provocation included leukotrienes (LTB(4) and 6-trans-LTB(4)), CYP-derivatives of linoleic acid (epoxides/diols), and IL-10.
  
  
  CONCLUSIONS
  Differences in asthmatic relative to healthy profiles suggest a role for 15-LOX products of both ω-6 and ω-3 origin in allergic inflammation. Prominent differences at baseline levels indicate that non-symptomatic asthmatics are subject to an underlying inflammatory condition not observed with other traditional mediators. Results suggest that oxylipin profiling may provide a sensitive means of characterizing low-level inflammation and that even individuals with mild disease display distinct phenotypic profiles, which may have clinical ramifications for disease.
authors.affiliation: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Lundström
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Källberg
authors.forename: Sarah
authors.initials: S
authors.lastname: Thunberg
authors.forename: Guro
authors.initials: G
authors.lastname: Gafvelin
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
authors.forename: Reidar
authors.initials: R
authors.lastname: Grönneberg
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.forename: Marianne
authors.initials: M
authors.lastname: van Hage
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.forename: Åsa M
authors.initials: ÅM
authors.lastname: Wheelock
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
mesh_terms: D000328:Adult; D000485:Allergens / Q000008:administration & dosage; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001249:Asthma / Q000150:complications / Q000276:immunology* / Q000378:metabolism*; D029662:Betula / Q000276:immunology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D016022:Case-Control Studies; D005227:Fatty Acids / Q000737:chemistry / Q000145:classification; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D008954:Models, Biological; D054883:Oxylipins / Q000737:chemistry / Q000378:metabolism; D011058:Pollen / Q000276:immunology; D006255:Rhinitis, Allergic, Seasonal / Q000150:complications / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000485:Allergens; D005227:Fatty Acids; D054883:Oxylipins; D001093:Arachidonate 15-Lipoxygenase