Excess deposition of type I collagen is characteristic of a number of fibrotic disorders including idiopathic pulmonary fibrosis, asthma, and scleroderma. Many fibrotic diseases have features of chronic inflammation. Reactive oxygen species (ROS) are abundant in inflammatory events, although the roles of ROS are not completely understood. TGF-Beta (TGF-B), considered to be the major pro-fibrotic effector, stimulates hydrogen peroxide (H202) production in myofibroblasts. The data presented here demonstrate, for the first time, that in myofibroblasts, H202 stimulates an increase in alpha1(I) collagen mRNA. Apigenin, a common dietary flavonoid with anti-inflammatory and anti-oxidant properties, blocks the TGF-B-stimulated increase of alpha1(I) collagen mRNA and the TGF-stimulated production of H202. The mechanism by which apigenin blocks the TGF-B-stimulated production of H202 remains unclear. Steady-state levels of alpha1(I) collagen mRNA are regulated by the rate of transcription of the alpha1(I) collagen gene and by the stability of the message. The investigators previously reported that inhibition of phosphatidylinositol 3- kinase (PI3K) decreased the stability of alpha1(I) collagen mRNA. They found that apigenin blocked the TGF-B-stimulated transcription of the alpha1(I)collagen gene and reduced the stability of the message. Most importantly, they found that in transgenic mice expressing the chloramphenicol acetyl transferase (CAT) reporter construct driven by the alpha1(I)collagen promoter, topically-applied apigenin blocked the CAT activity of skin samples. Thus, it appears that apigenin is a potent downregulator of alpha1(I) collagen expression both in vitro and in vivo. This proposal will (Aim 1) test the hypothesis that an apigenin-rich diet will attenuate the development of fibrosis and (Aim 2) identify the apigenin-sensitive mechanism by which TGF-B stimulates production of H202 and test the hypothesis that alpha1(I) collagen mRNA stability is modulated through PI3K activity.
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| Rishikof, David C; Ricupero, Dennis A; Liu, Hanqiao et al. (2004) Phenylbutyrate decreases type I collagen production in human lung fibroblasts. J Cell Biochem 91:740-8 |
