Biphasic Late Airway Hyperresponsiveness in a Murine Model of Asthma

• Published in: International archives of allergy and immunology Vol. 160; no. 2; pp. 173 - 183
• Main Authors: Kim, Hae-Kyoung, Lee, Chang-Hoon, Kim, Jun-Mo, Ayush, Otgonzaya, Im, Suhn-Yong, Lee, Hern-Ku
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2013
• Subjects: Allergens - immunology; Animals; Asthma; Asthma - immunology; Asthma - physiopathology; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - physiopathology; Cytokines; Cytokines - immunology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Immunoblotting; Inflammation - immunology; Inflammation - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Original Paper; Ovalbumin - immunology; Rodents; Th2 Cells - immunology; Tumor Necrosis Factor-alpha - immunology; Leukotriene B4; Tumor necrosis factor; Biphasic late airway hyperresponsiveness; Cytosolic phospholipase A2; Asthma
• ISSN: 1018-2438; 1423-0097
• DOI: 10.1159/000341645

Background: Nonspecific airway hyperresponsiveness (AHR) is one of the cardinal features of bronchial asthma. Early AHR is caused by chemical mediators released from pulmonary mast cells activated in an IgE-dependent way. However, the mechanism of late AHR remains unclear. Methods: Features of airway allergic inflammation were analyzed, including antigen-induced AHR, using a murine model of asthma. The model was suitable for examining the sequential early molecular events occurring after the initial airway exposure to antigen. Results: AHR increased at 10–12 h after airway challenge, followed by the second-phase response, which was larger and broader in resistance at 18–30 h. Pretreatment of sensitized animals with anti-tumor necrosis factor (TNF) before airway challenge or induction of allergic asthma in TNF –/– mice resulted in abrogation of the first-phase late AHR. Intratracheal instillation of TNF induced a single peak of AHR at 10 h. IgE and IgG immune complexes induced the development of the first-phase late AHR by TNF production. Pretreatment with cytosolic phospholipase inhibitor and 5-lipoxygenase inhibitors abolished the first-phase late AHR as well as the leukotriene B 4 levels in the airway. CpG-oligodeoxynucleotide (ODN) pretreatment reduced airway levels of Th2 cytokines, eosinophil infiltration and second-phase late AHR. However, CpG-ODN did not reduce TNF levels or the magnitude of first-phase late AHR. Conclusion: Biphasic late AHR occurs in a murine model of asthma. First- and second-phase late AHR is caused by TNF and Th2 response, respectively.