title: Anti-tumor necrosis factor-alpha antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust.
abstract: OBJECTIVE
  Recent studies documented that sensitization and exposure to cockroach allergens significantly increase children's asthma morbidity as well as severity, especially among inner city children. TNF-alpha has been postulated to be a critical mediator directly contributing to the bronchopulmonary inflammation and airway hyper-responsiveness in asthma. This study investigated whether an anti-TNF-alpha antibody would inhibit pulmonary inflammation and methacholine (Mch) hyper-responsiveness in a mouse model of asthma induced by a house dust extract containing both endotoxin and cockroach allergens.
  
  
  METHODS
  A house dust sample was extracted with phosphate-buffered saline and then used for immunization and two additional pulmonary challenges of BALB/c mice. Mice were treated with an intravenous injection of anti-TNF-alpha antibody or control antibody 1 h before each pulmonary challenge.
  
  
  RESULTS
  In a kinetic study, TNF-alpha levels within the bronchoalveolar lavage (BAL) fluid increased quickly peaking at 2 h while BAL levels of IL-4, IL-5, and IL-13 peaked at later time-points. Mch hyper-responsiveness was measured 24 h after the last challenge, and mice were killed 24 h later. TNF inhibition resulted in an augmentation of these Th2 cytokines. However, the allergic pulmonary inflammation was significantly reduced by anti-TNF-alpha antibody treatment as demonstrated by a substantial reduction in the number of BAL eosinophils, lymphocytes, macrophages, and neutrophils compared with rat IgG-treated mice. Mch hyper-responsiveness was also significantly reduced in anti-TNF-alpha antibody-treated mice and the pulmonary histology was also significantly improved. Inhibition of TNF significantly reduced eotaxin levels within the lung, suggesting a potential mechanism for the beneficial effects. These data indicate that anti-TNF-alpha antibody can reduce the inflammation and pathophysiology of asthma in a murine model of asthma induced by a house dust extract.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. jiyoukim@umich.edu
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: McKinley
authors.forename: S
authors.initials: S
authors.lastname: Natarajan
authors.forename: G L
authors.initials: GL
authors.lastname: Bolgos
authors.forename: J
authors.initials: J
authors.lastname: Siddiqui
authors.forename: S
authors.initials: S
authors.lastname: Copeland
authors.forename: D G
authors.initials: DG
authors.lastname: Remick
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001249:Asthma / Q000276:immunology / Q000628:therapy*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016085:Bronchoconstrictor Agents; D003058:Cockroaches; D016207:Cytokines / Q000097:blood; D004391:Dust; D004731:Endotoxins; D005260:Female; D008168:Lung / Q000276:immunology*; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D016085:Bronchoconstrictor Agents; D016207:Cytokines; D004391:Dust; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride