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Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP).We examined the effect of GATA-3 overexpression on the development of HP in mice.Wild-type C57BL/6 mice and GATA-3-overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmer's lung.Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN)-gamma in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3-overexpressing mice. The induction of T-bet and IFN-gamma genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3-overexpressing mice after antigen exposure. Supplementation with recombinant IFN-gamma enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-gamma production predominantly occurred in CD4+ T cells, nude mice were transferred with CD4+ T cells from either wild-type or GATA-3-overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4+ T cells from GATA-3-overexpressing mice than in those with wild-type CD4+ T cells, with a reduction of lung IFN-gamma level.These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.

Airway remodeling is an important feature of chronic asthma that causes irreversible airflow obstruction. Although asthma is considered to be a Th2 disease, the role of T-bet and GATA-3, the key transcription factors for differentiation toward Th1 and Th2 cells, in the pathogenesis of airway remodeling is poorly understood.We therefore examined the effects of GATA-3 or T-bet induction of Th1/Th2 bias on the development of airway remodeling in mice.The development of airway remodeling after repeated allergen challenges was analyzed using transgenic mice overexpressing either GATA-3 or T-bet.The degrees of subepithelial fibrosis and airway smooth muscle hyperplasia after repeated allergen exposure were significantly enhanced in mice overexpressing GATA-3, compared with wild-type mice. Allergen-induced goblet cell hyperplasia and mucus hypersecretion were significantly lower in mice overexpressing T-bet than in wild-type mice. Eosinophilic airway inflammation increased in mice overexpressing GATA-3, but decreased in mice overexpressing T-bet after repeated allergen exposure. Cytokine analysis revealed that the Th1/Th2 cytokine balance shifted to Th2 in lung homogenates and lung T cells of mice overexpressing GATA-3, whereas this balance shifted to Th1 in those of mice overexpressing T-bet after allergen exposure. Lung transforming growth factor-beta and eotaxin levels were associated with the degree of subepithelial fibrosis and eosinophilic airway inflammation, respectively.Overall, the results indicate that development of airway remodeling is regulated by the lung Th1/Th2 bias induced by GATA-3 and T-bet.

Acute lung injury (ALI) is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Recent studies demonstrated that cyclooxygenase-2 (COX-2) induced at the late phase of inflammation aids in the resolution of inflammation by generating 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2). Transcription factor Nrf2 is activated by electrophiles and exerts antiinflammatory effects by inducing the gene expression of antioxidant and detoxification enzymes.Because 15d-PGJ2 is an endogenous electrophile, we hypothesized that it protects against ALI by activating Nrf2.To test this hypothesis, we generated a reversible ALI model by intratracheal injection of carrageenin, an inducer of acute inflammation, whose stimulation has been known to induce COX-2.We found that ALI induced by carrageenin was markedly exacerbated in Nrf2-knockout mice, compared with wild-type mice. Analysis of bronchoalveolar lavage fluids also revealed that the magnitude and the duration of acute inflammation, indicated by albumin concentration and the number of neutrophils, were significantly enhanced in Nrf2-knockout mice. Treatment of wild-type mice with NS-398, a selective COX-2 inhibitor, significantly exacerbated ALI to the level of Nrf2-knockout mice. In the lungs of NS-398-treated wild-type mice, both the accumulation of 15d-PGJ2 and the induction of Nrf2 target antioxidant genes were significantly attenuated. Exogenous administration of 15d-PGJ2 reversed the exacerbating effects of NS-398 with the induction of antioxidant genes.These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.