Citations

ABSTRACT TGF‐β plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF‐β in fibroblast lines and primary cells and is required for the profibrotic effects of TGF‐β. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis‐inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up‐regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet‐derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGFβ–driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF‐β signaling and present opportunities for potential therapeutic intervention.—Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.‐H., Jung, M.‐Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up‐regulation of glucose transporter 1 by TGF‐β involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB J. 30, 3733–3744 (2016) www.fasebj.org

AbstractBackgroundHigh‐resolution manometry using the Chicago classification, which utilizes parameters including integrated relaxation pressure (IRP), distal contractile integral (DCI), and contractile front velocity (CFV), shows better diagnostic ability than previous conventional criteria. However, the current normal cut‐off values for the Chicago classification are based on individuals aged 19–48 years and do not include older people. Here, we aimed to assess the normal values for the Chicago classification in individuals aged 20–67 years and compare the parameters across age groups.MethodsFifty‐four asymptomatic healthy individuals (27 male and 27 female; age range. 20–67 years) were prospectively enrolled. To evaluate the effect of age and sex on manometric profiles, we attempted to enroll equal numbers of male and female subjects for each decade. Manometry was performed in both the supine and sitting positions.Key ResultsThe distal latency (DL) was significantly shorter with increasing age in both measurement positions. Furthermore, IRP was significantly higher with increasing age in both positions. Spearman's ranked correlation coefficient analysis indicated that DCI and IRP in both positions were positively correlated with age.Conclusions & InferencesAge affects the key parameters currently used in the Chicago classification, including IRP, DCI, and DL. Larger prospective studies with older subjects are needed to determine the age‐related normal values for the Chicago classification system.