Genistein and Asthma Pathogenesis

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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.