Genistein and Asthma Pathogenesis

描述（由申请人提供）：哮喘气道重塑导致不可逆的气流阻塞。染料木素是一种在大豆中发现的膳食异黄酮和酪氨酸激酶抑制剂。一项流行病学研究表明，哮喘患者摄入较高的染料木素可减少气流阻塞。在动物哮喘模型中，染料木素可减少支气管收缩、肺白三烯水平和气道嗜酸性粒细胞增多。我们发现染料木素损害嗜酸性粒细胞白三烯合成并抑制成纤维细胞向肌成纤维细胞的转化，这是气道重塑的一个关键表型变化。我们假设染料木素通过抑制tgf - β 1-和整合素诱导的细胞内信号传导，阻断肺成纤维细胞向肌成纤维细胞的转化。我们测试了染料木黄酮抑制tgf - β 1刺激的smad转录因子、p38和JNK激活的能力。我们评估了染料木素对tgf - β 1和整合素刺激的局灶黏附激酶（FAK）和src激活的影响，以及阻断FAK和src对JNK和p38的下游影响。探索这些机制将扩大酪氨酸激酶抑制作为哮喘气道重塑治疗方法的科学依据，并为进一步研究大豆异黄酮的治疗作用提供依据。

DESCRIPTION (provided by applicant): Airway remodeling in asthma results in irreversible airflow obstruction. Genistein is a dietary isoflavone and tyrosine kinase inhibitor found in soy. An epidemiologic study revealed that subjects with asthma having higher genistein intake have less airflow obstruction. In animal asthma models, genistein reduces bronchoconstriction, lung leukotriene levels, and airway eosinophilia. We found that genistein impairs eosinophil leukotriene synthesis and inhibits the transformation of fibroblasts to myofibroblasts, a key phenotypic change of the remodeled airway. We hypothesize that genistein blocks the transformation of lung fibroblasts to myofibroblasts by inhibiting TGF-beta1- and integrin-induced intracellular signaling. We test genistein's ability to inhibit TGF-beta1 stimulated activation of Smad-transcription factors, p38, and JNK. We evaluate genistein's effects on TGF-beta1- and integrin-stimulated activation of focal adhesion kinase (FAK) and src, and the downstream consequences of blocking FAK and src on JNK and p38. Exploring these mechanisms will expand the scientific rationale for tyrosine kinase inhibition as a therapeutic approach to asthmatic airway remodeling, and justify further study of the therapeutic role of soy isoflavones.