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Anti-tumor necrosis factor-α antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust


Jiyoun Kim, Department of Pathology, University of Michigan Medical School, M2210 Med Sci I, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA.


Background/Aims 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-α 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-α 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-α antibody or control antibody 1  h before each pulmonary challenge.

Results In a kinetic study, TNF-α 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-α 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-α 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-α antibody can reduce the inflammation and pathophysiology of asthma in a murine model of asthma induced by a house dust extract.