Molecular analysis of relationship between airway hyperreactivity and inflammation

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Analysis using cDNA array revealed that CCL21 (formerly secondary lymphoid tissue chemokine, SLC) and CCL19 were significantly increased at 6 hours after allergen inhalation. CCL21 is a key chemokine in the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs, which is a critical process in antigen-specific T-cell activation. In the study, we investigated the role of CCL21 in airway inflammation in asthma using BALB/c-plt/plt mice (plt mice), which possess genetic defects in expression of both CCL21 and CCL19. Plt and control BALB/c mice were immunized with ovalbumin (OVA) and alum four times and thereafter were subjected to a two-week regimen of OVA inhalation. Although airway inflammation and response to acetylcholine were significantly reduced compared to BALB/c mice, significant eosinophilic inflammation and hyperresponsivenss were also observed in plt mice. Four weeks after cessation of inhalation, airway inflammation and hyperrespon … More siveness in plt mice were greater than in BALB/c mice. To clarify the mechanisms of delay in resolution of airway inflammation, we performed flow cytometric analysis to assess CCR7, receptor for CCL19 and CCL21 on T cell, because it has been reported that CCR7 expression is critical for T cell exit from peripheral tissues. There were CD4+CCR7+ cells but majority was CD4+CCR7- cells in the airway of plt mice. Seven days after cessation of OVA inhalation, number of CD25 positive CD4 cells and IL-10 production were significantly lesser in plt mice compared to BALB/c mice in the BALF. In conclusion, CCL21 and CCL19 were critical for not only induction but also resolution of airway inflammation.In order to clarify the role of T cell for airway hyperreactivity, we focused on GATA-3, which is essential for Th2 cells to produce Th2 cytokines and aimed to clarify the role of GATA-3 hyperexpressive T cells in the pathophysiology of bronchial asthma in vivo. Double transgenic mice carrying the GATA-3 gene and the ovalbumin (OVA)-specific T cell receptor gene (GATA-3-Tg (+)) were used. As a results, GATA-3-Tg (+) mice exhibited significantly higher IL-13 and IL-4 protein at the airway. Although there was no difference in infiltrated cells between GATA-3-Tg(+) and GATA-3-Tg(-) and no significant increase in IgE level in either group compared to non-treated mice, the response after acetylcholine inhalation was significantly elevated in GATA-3-Tg(+) than in GATA-3-Tg(-) on the seventh day of intranasal treatment with OVA. This hyperresponsiveness was inhibited by 5-lipoxygenase inhibitor. In conclusion, airway hyperresponsiveness, a characteristic of bronchial asthma, was induced by controlling lymphocytes at the transcriptional level in vivo. Less