Metformin reverses established lung fibrosis in a bleomycin model

1.Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic illness. Nat. Med. 18, 1028–1040 (2012).2.Lumeng, C. N. & Saltiel, A. R. Inflammatory hyperlinks between weight problems and metabolic illness. J. Clin. Make investments. 121, 2111–2117 (2011).Three.O’Neill, L. A. & Hardie, D. G. Metabolism of irritation restricted by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).Four.Eltzschig, H. Okay. & Eckle, T. Ischemia and reperfusion—from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).5.Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and power sensor that maintains power homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).6.Beers, M. F. & Morrisey, E. E. The three R’s of lung well being and illness: restore, reworking, and regeneration. J. Clin. Make investments. 121, 2065–2073 (2011).7.Thannickal, V. J., Zhou, Y., Gaggar, A. & Duncan, S. R. Fibrosis: final and proximate causes. J. Clin. Make investments. 124, 4673–4677 (2014).eight.Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue restore and fibrosis. Annu. Rev. Pathol. eight, 241–276 (2013).9.Bueno, M. et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin. Make investments. 125, 521–538 (2015).10.Kobayashi, Okay. et al. Involvement of PARK2-mediated mitophagy in idiopathic pulmonary fibrosis pathogenesis. J. Immunol. 197, 504–516 (2016).11.Bernard, Okay. et al. Metabolic reprogramming is required for myofibroblast contractility and differentiation. J. Biol. Chem. 290, 25427–25438 (2015).12.Ramos, C. et al. Fibroblasts from idiopathic pulmonary fibrosis and regular lungs differ in progress price, apoptosis, and tissue inhibitor of metalloproteinases expression. Am. J. Respir. Cell Mol. Biol. 24, 591–598 (2001).13.Romero, Y. et al. mTORC1 activation decreases autophagy in getting old and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Getting old Cell 15, 1103–1112 (2016).14.Ashley, S. L. et al. Concentrating on inhibitor of apoptosis proteins protects from bleomycin-induced lung fibrosis. Am. J. Respir. Cell Mol. Biol. 54, 482–492 (2016).15.Hecker, L. et al. Reversal of persistent fibrosis in getting old by focusing on Nox4-Nrf2 redox imbalance. Sci. Transl. Med. 6, 231ra247 (2014).16.Inoki, Okay., Kim, J. & Guan, Okay. L. AMPK and mTOR in mobile power homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400 (2012).17.Shaw, R. J. Metformin trims fat to revive insulin sensitivity. Nat. Med. 19, 1570–1572 (2013).18.Riera, C. E. & Dillin, A. Can getting old be ‘drugged’? Nat. Med. 21, 1400–1405 (2015).19.Finkel, T. The metabolic regulation of getting old. Nat. Med. 21, 1416–1423 (2015).20.Burkewitz, Okay., Zhang, Y. & Mair, W. B. AMPK on the nexus of energetics and getting old. Cell Metab. 20, 10–25 (2014).21.Salminen, A. & Kaarniranta, Okay. AMP-activated protein kinase (AMPK) controls the getting old course of by way of an built-in signaling community. Ageing Res. Rev. 11, 230–241 (2012).22.Park, C. S. et al. Metformin reduces airway irritation and reworking by way of activation of AMP-activated protein kinase. Biochem. Pharmacol. 84, 1660–1670 (2012).23.Liu, Z. et al. AMP-activated protein kinase and glycogen synthase kinase 3β modulate the severity of sepsis-induced lung harm. Mol. Med. 21, 937–950 (2015).24.Sato, N. et al. Metformin attenuates lung fibrosis improvement by way of NOX4 suppression. Respir. Res. 17, 107 (2016).25.Mishra, R. et al. AMP-activated protein kinase inhibits reworking progress factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J. Biol. Chem. 283, 10461–10469 (2008).26.Thakur, S. et al. Activation of AMP-activated protein kinase prevents TGF-β1-induced epithelial-mesenchymal transition and myofibroblast activation. Am. J. Pathol. 185, 2168–2180 (2015).27.Lim, J. Y., Oh, M. A., Kim, W. H., Sohn, H. Y. & Park, S. I. AMP-activated protein kinase inhibits TGF-β-induced fibrogenic responses of hepatic stellate cells by focusing on transcriptional coactivator p300. J. Cell Physiol. 227, 1081–1089 (2012).28.Li, L. et al. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway. Oncotarget 6, 43605–43619 (2015).29.Park, I. H. et al. Metformin reduces TGF-β1-induced extracellular matrix manufacturing in nasal polyp-derived fibroblasts. Otolaryngol. Head Neck Surg. 150, 148–153 (2014).30.Kottmann, R. M. et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation by way of pH-dependent activation of remodeling progress factor-beta. Am. J. Respir. Crit. Care Med. 186, 740–751 (2012).31.Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects power sensing to mitophagy. Science 331, 456–461 (2011).32.Parsons, M. J. & Inexperienced, D. R. Mitochondria in cell demise. Essays Biochem. 47, 99–114 (2010).33.Tait, S. W. & Inexperienced, D. R. Mitochondria and cell demise: outer membrane permeabilization and past. Nat. Rev. Mol. Cell Biol. 11, 621–632 (2010).34.Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic swap required for mobile adaptation to hypoxia. Cell Metab. Three, 177–185 (2006).35.Spoden, G. A. et al. Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell measurement and apoptotic cell demise depending on glucose provide. Exp. Cell Res. 315, 2765–2774 (2009).36.Horowitz, J. C. et al. Activation of the pro-survival phosphatidylinositol Three-kinase/AKT pathway by reworking progress factor-β1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine progress issue. J. Biol. Chem. 279, 1359–1367 (2004).37.Foretz, M., Guigas, B., Bertrand, L., Pollak, M. & Viollet, B. Metformin: from mechanisms of motion to therapies. Cell Metab. 20, 953–966 (2014).38.Knowler, W. C. et al. Discount within the incidence of kind 2 diabetes with way of life intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).39.Yu, G. et al. Thyroid hormone inhibits lung fibrosis in mice by bettering epithelial mitochondrial perform. Nat. Med. 24, 39–49 (2018).40.Jiang, S. et al. Mitochondria and AMP-activated protein kinase-dependent mechanism of efferocytosis. J. Biol. Chem. 288, 26013–26026 (2013).41.Jian, M. Y., Alexeyev, M. F., Wolkowicz, P. E., Zmijewski, J. W. & Creighton, J. R. Metformin-stimulated AMPK-α1 promotes microvascular restore in acute lung harm. Am. J. Physiol. Lung Cell Mol. Physiol. 305, L844–855 (2013).42.Hecker, L. et al. NADPH oxidase-Four mediates myofibroblast activation and fibrogenic responses to lung harm. Nat. Med. 15, 1077–1081 (2009).43.Jiang, S. et al. Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular entice formation and will increase severity of acute lung harm. J. Immunol. 192, 4795–4803 (2014).44.Franco-Barraza, J., Beacham, D. A., Amatangelo, M. D., & Cukierman, E. Preparation of extracellular matrices produced by cultured and first fibroblasts. Curr. Protoc. Cell Biol. 71, 10.9.1–10.9.34 (2016).45.Hill, B. G. et al. Integration of mobile bioenergetics with mitochondrial high quality management and autophagy. Biol. Chem. 393, 1485–1512 (2012).46.Graham, L. & Orenstein, J.M. Processing tissue and cells for transmission electron microscopy in diagnostic pathology and analysis. Nat. Protoc. 2, 2439–2450 (2007).


Please enter your comment!
Please enter your name here