title: Systemic FasL neutralization increases eosinophilic inflammation in a mouse model of asthma.
abstract: BACKGROUND
  Eosinophils and lymphocytes are pathogenically important in allergic inflammation and sensitive to Fas-mediated apoptosis. Fas ligand (FasL) activity therefore should play a role in regulating the allergic immune response. We aimed to characterize the role of FasL expression in airway eosinophilia in Aspergillus fumigatus (Af)-induced sensitization and to determine whether FasL neutralization alters the inflammatory response.
  
  
  METHODS
  Sensitized Balb/c mice were killed before (day 0) and 1, 7 and 10 days after a single intranasal challenge with Af. Animals received either neutralizing antibody to FasL (clone MFL4) or irrelevant hamster IgG via intraperitoneal injection on days -1 and 5. FasL expression, BAL and tissue inflammatory cell and cytokine profile, and apoptosis were assessed.
  
  
  RESULTS
  Postchallenge FasL gene expression in BAL cells and TUNEL positivity in the airways coincided with the height of inflammatory cell influx on day 1, while soluble FasL protein was released on day 7, preceding resolution of the inflammatory changes. Although eosinophil numbers showed a negative correlation with soluble FasL levels in the airways, MBP(+) eosinophils remained TUNEL negative in the submucosal tissue, throughout the 10-day period after Af challenge. Systemic FasL neutralization significantly enhanced BAL and tissue eosinophil counts. This effect was associated with increased activation of T cells and release of IL-5, IL-9, and GM-CSF in the BAL fluid of mice, indicating an involvement of pro-eosinophilic survival pathways.
  
  
  CONCLUSIONS
  FasL activity may play an active role in resolving eosinophilic inflammation through regulating T cells and pro-eosinophilic cytokine release during the allergic airway response.
authors.affiliation: Pulmonary, Allergy and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: F A
authors.initials: FA
authors.lastname: Almeida
authors.forename: S
authors.initials: S
authors.lastname: Kierstein
authors.forename: L
authors.initials: L
authors.lastname: Hortobagyi
authors.forename: T
authors.initials: T
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Larkin
authors.forename: J
authors.initials: J
authors.lastname: Peterson
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: J G
authors.initials: JG
authors.lastname: Zangrilli
authors.forename: A
authors.initials: A
authors.lastname: Haczku
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D006224:Cricetinae; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000276:immunology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse