121 Ovalbumin-induced Bronchial Asthma is Compromised in Apoptosis Signal-Regulating Kinase-Deficient Mice

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen –activated protein (MAP) kinase kinase kinases (MAP3Ks) protein family, plays a crucial role in the induction of apoptosis and inflammation in some cell types. Allergic asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammatory cell infiltration, and airway remodeling. In the present study, we examined whether ASK1 is involved in the induction of bronchial asthma using a mouse model of airway inflammation. METHODS: ASK1-deficient (ASK1−/−) and wild-type (WT) control mice were sensitized with ovalbumin (OVA) in saline intraperitoneally on consecutive 7 days. Eighteen days later, mice received intranasal administration of OVA aerosol and were assayed for AHR, cytokine production, cell proliferation, antibody (Ab) production, and lung tissue histopathology at 24 hours after the last serial OVA administration. Levels of Ab and cytokines were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Control WT mice showed inflammatory infiltrates in airways in response to OVA to a greater extent than ASK1−/− mice. The number of cells, especially eosinophils accumulating in airways, was reduced in ASK1−/− mice relative to control mice. OVA-induced AHR is also compromised in ASK1−/− mice. Anti-OVA IgE Ab production in ASK1−/− mice was substantially reduced, although levels of other isotypes were comparable to those in control mice. Levels of some Th2 cytokines (IL-5 and IL-13) and pro-inflammatory cytokine TNF-a in BAL fluid from ASK1−/− mice were substantially diminished relative to control, although a comparable level of a typical Th2 cytokine IL-4 and anti-inflammatory cytokine IL-10 was produced. Although the BAL fluid TNF-a levels from ASK1−/− mice were severely diminished, lymph node cells from ASK1−/− mice produced comparable levels of TNF-a to WT in vitro. Intranasal administration of recombinant TNF-a caused a comparable increase in AHR between ASK1−/− and WT mice, whereas the TNF-a -induced accumulation of inflammatory cells was severely reduced in ASK1−/− mice. CONCLUSIONS: ASK1 appears to be involved in the induction of OVA-induced bronchial asthma, probably through cytokine production such as TNF-a and IL-13. Moreover, TNF-a sensitivity in response to OVA is also regulated by ASK1.