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• W2891540723 abstract "Idiopathic pulmonary fibrosis (IPF) remains an important medical challenge, but recent translational data have provided clues implicating deficient AMPK signaling in persistently activated myelofibroblasts within fibrotic foci. A new study in Nature Medicine reports that pharmacological activation of AMPK with metformin can reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts. Idiopathic pulmonary fibrosis (IPF) remains an important medical challenge, but recent translational data have provided clues implicating deficient AMPK signaling in persistently activated myelofibroblasts within fibrotic foci. A new study in Nature Medicine reports that pharmacological activation of AMPK with metformin can reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts. Idiopathic pulmonary fibrosis (IPF) remains a grievous and recalcitrant problem with an abysmal prognosis (Verma and Slutsky, 2007Verma S. Slutsky A.S. Idiopathic pulmonary fibrosis--new insights.N. Engl. J. Med. 2007; 356: 1370-1372Crossref PubMed Scopus (52) Google Scholar). Until about 4 years ago, the goals of care for patients with IPF were modest: to reduce signs and symptoms and improve quality of life, as median expected survival was 3–5 years. Prednisone, azathioprine, N-acetylcysteine (NAC), and supportive care with oxygen therapy and pulmonary rehabilitation was the mainstay of treatment and did not significantly increase life expectancy. Lung transplantation represented a final option for those patients who were deemed appropriate. Over the past 4 short years, the landscape for IPF has changed dramatically. Disappointment created by a series of negative anti-inflammatory and immunosuppressive trials has been followed by the completion of successful randomized, controlled trials specifically targeting mediators of repair and remodeling, resulting in the licensing of two novel drugs for this disease and a re-evaluation of the central thesis regarding the pathogenesis of fibrosis (Raghu et al., 2015Raghu G. Rochwerg B. Zhang Y. Garcia C.A. Azuma A. Behr J. Brozek J.L. Collard H.R. Cunningham W. Homma S. et al.American Thoracic SocietyEuropean Respiratory societyJapanese Respiratory SocietyLatin American Thoracic AssociationAn official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.Am. J. Respir. Crit. Care Med. 2015; 192: e3-e19Crossref PubMed Scopus (1303) Google Scholar). Pathological fibrosis is the final common pathway and histological manifestation of a dysfunctional repair response to tissue injury and was, therefore, classically believed to be driven by underlying inflammation. Early termination for therapeutic failure, and in some cases increased harm, of the PANTHER-IPF trial triple-therapy arm (combination of prednisolone, azathioprine, and NAC), the modified PANTHER-IPF trial, IFN-γ, and TNF-α, antagonist contributed to the recognition that corticosteroids and steroid-sparing agents may actually increase mortality in IPF, underscoring a tectonic shift in paradigm where cellular repair and remodeling takes center stage, not as a consequence of inflammation, but as an independent and critical determinant of fibrosis. The success of the first phase II trial of an anti-fibrotic agent, intracellular tyrosine kinase inhibitor (nintedanib), was quickly followed by the phase III INPULSIS trials (INPULSIS-1 and INPULSIS-2). Although not powered to detect a difference in mortality, nintedanib showed a significant reduction in forced vital capacity (FVC) decline. In parallel, results of three phase II trials of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), thought to inhibit both production and activity of TGF-β, spurred a first phase III study showing a significant reduction in FVC decline. This was followed by two CAPACITY trials (004 and 006) and licensing of the new anti-fibrotic agent in Europe. In the U.S., the Food and Drug Administration requested a subsequent phase III trial (ASCEND). In a pre-specified pooled analysis, pirfenidone reduced the risk of death at 1 year by 48% compared to placebo and the risk of treatment-emergent death by 68%, firmly establishing anti-fibrotic agents as the new standard of care. While the precise mechanism(s) of action for both nintedanib and pirfenidone remain incompletely understood, it seems clear that both drugs prevent progression of fibrosis but do not reverse established fibrosis, raising the question of what drives fibrosis and how to reverse established fibrosis. This critical question was recently tackled by Rangarajan et al., 2018Rangarajan S. Bone N.B. Zmijewska A.A. Jiang S. Park D.W. Bernard K. Locy M.L. Ravi S. Deshane J. Mannon R.B. et al.Metformin reverses established lung fibrosis in a bleomycin model.Nat. Med. 2018; 24: 1121-1127Crossref PubMed Scopus (268) Google Scholar to demonstrate that resolution of lung fibrosis can be accelerated by targeting the metabolic reprogramming that regulates abnormal myofibroblast differentiation and function in IPF. IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, including uncontrolled proliferation of lung (myo) fibroblasts and excessive deposition of extracellular matrix proteins in the interstitial space. While initially much of the mechanistic understanding was derived from hypotheses generated from animal models, in recent decades new insights derived from humans with IPF have taken precedence and contributed to a shift in our understanding of pulmonary fibrosis. Fibrotic lung tissue in IPF has been shown to have increased metabolic activity associated with disease progression and mortality. Metabolomics has linked alterations in glucose metabolic pathways to structural remodeling of the lungs. Expression profiling analysis demonstrated abnormalities in metabolic pathways, including glycolysis, mitochondrial β-oxidation, glutamate/aspartate metabolism, TCA cycle, glutathione biosynthesis, adenosine triphosphate degradation, and ornithine aminotransferase pathways. Rangarajan et al.’s fundamental contribution to the advancement of the field is in contextualizing multiple lines of evidence into a cohesive hypothesis for progression of fibrosis in patients with IPF; adenosine monophosphate (AMP)-activated protein kinase (AMPK), the cellular bioenergetic sensor and metabolic regulator that controls the switch from anabolic to catabolic metabolism, is significantly downregulated in fibrotic regions associated with metabolically active and apoptosis-resistant myofibroblasts. The authors demonstrate a significant decrease in AMPK activity in the lungs from patients with IPF. Furthermore, isolated human IPF fibroblasts demonstrate lower activity of AMPK with pronounced activation of mTOR and HIF-1α and reduced autophagic flux. Pharmacological activation of AMPK with metformin enhances mitochondrial biogenesis, normalizes sensitivity to apoptosis, and—in a mouse model of bleomycin-induced lung injury—reverses established fibrosis (Figure 1). Preclinical studies have suggested that metformin has anti-fibrotic and anti-inflammatory effects. Importantly, metformin has been found to attenuate lung fibrosis by inhibiting TGF-β via AMPK activation (Rangarajan et al., 2016Rangarajan S. Locy M.L. Luckhardt T.R. Thannickal V.J. Targeted therapy for idiopathic pulmonary fibrosis: where to now?.Drugs. 2016; 76: 291-300Crossref PubMed Scopus (36) Google Scholar). Rangarajan et al.’s findings are in keeping with Yu et al.’s integrated model of pulmonary fibrosis (Yu et al., 2018Yu G. Ibarra G.H. Kaminski N. Fibrosis: lessons from OMICS analyses of the human lung.Matrix Biol. 2018; 68-69: 422-434Crossref PubMed Scopus (29) Google Scholar). In this model, genetic susceptibility and increased environmental stress generate a disproportionate metabolic and replicative stress on the alveolar unit, driving an abnormal response to injury: instead of proliferating normally and participating in a self-limited wound-healing response, cells may develop a senescence-associated secretory phenotype (SASP), characterized by growth arrest, extracellular matrix deposition, metabolic derangements, mitochondrial dysfunction with abnormal autophagy and mitophagy, and apoptosis resistance. While the accelerated senescence hypothesis is gaining significant traction in the field of IPF (Cazzola et al., 2018Cazzola M. Matera M.G. Rogliani P. Calzetta L. Senolytic drugs in respiratory medicine: is it an appropriate therapeutic approach?.Expert Opin. Investig. Drugs. 2018; 27: 573-581Crossref PubMed Scopus (15) Google Scholar, Waters et al., 2018Waters D.W. Blokland K.E.C. Pathinayake P.S. Burgess J.K. Mutsaers S.E. Prele C.M. Schuliga M. Grainge C.L. Knight D.A. Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis.Am. J. Physiol. Lung Cell. Mol. Physiol. 2018; 315: L162-L172Crossref PubMed Scopus (80) Google Scholar, Zank et al., 2018Zank D.C. Bueno M. Mora A.L. Rojas M. Idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics.Front Med. (Lausanne). 2018; 5: 10Crossref PubMed Scopus (91) Google Scholar), how metabolic reprograming is established remains an open question, but likely involves epigenetic reprogramming (Rabinovich et al., 2012Rabinovich E.I. Selman M. Kaminski N. Epigenomics of idiopathic pulmonary fibrosis: evaluating the first steps.Am. J. Respir. Crit. Care Med. 2012; 186: 473-475Crossref PubMed Scopus (18) Google Scholar). Despite a burgeoning enthusiasm for this translational work, moving findings to the clinic might be challenging. Spagnolo et al., 2018Spagnolo P. Kreuter M. Maher T.M. Wuyts W. Bonella F. Corte T.J. Kopf S. Weycker D. Kirchgaessler K.U. Ryerson C.J. Metformin does not affect clinically relevant outcomes in patients with idiopathic pulmonary fibrosis.Respiration. 2018; (Published online July 19, 2018)https://doi.org/10.1159/000489668Crossref Scopus (34) Google Scholar recently published a post hoc analysis of IPF patients enrolled in CAPACITY (004 and 006) and ASCEND who were prescribed metformin for comorbid diabetes. For the primary outcome analysis of disease progression (decline in FVC), the unadjusted 1-year analyses demonstrated no significant differences in disease progression. In fact, a slightly higher proportion of metformin users compared with non-users had a relative FVC decline of ≥5%, which supported the conclusion that metformin has no effect on clinically relevant outcomes in patients with IPF. Though previous studies have strongly suggested a role for immunometabolism in fibrosis, the study by Rangarajan et al. provides much-needed novel insight into our understanding of fibrosis as a disease of dysregulated cellular (myofibroblast) metabolism. The concept that an old drug like metformin that is cheap and widely available may, through AMPK activation, stimulation of autophagy, and induction of mitochondrial biogenesis, essentially rehabilitate apoptotic sensitivity and promote fibrosis resolution is tantalizing. Clearly, such provocative data call for more in-depth clinical trial evaluation of metformin in select patients with IPF. Concerted interest in metabolic remodeling as a potential target for therapy has spurred novel clinical trials based on metabolic targets. PBI-4050 (3-pentylbenzeneacetic acid sodium salt) is a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward the G protein receptors GPR40 and GPR84. By binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in various organs, and in a phase II study (NCT02538536), PBI-4050 was shown to stabilize FVC decline (Gagnon et al., 2018Gagnon L. Leduc M. Thibodeau J.F. Zhang M.Z. Grouix B. Sarra-Bournet F. Gagnon W. Hince K. Tremblay M. Geerts L. et al.A newly discovered antifibrotic pathway regulated by two fatty acid receptors: GPR40 and GPR84.Am. J. Pathol. 2018; 188: 1132-1148Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, Li et al., 2018Li Y. Chung S. Li Z. Overstreet J.M. Gagnon L. Grouix B. Leduc M. Laurin P. Zhang M.Z. Harris R.C. Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control.JCI Insight. 2018; 3: 120365Crossref PubMed Scopus (15) Google Scholar). Ironically, despite much criticism incurred by the inflammation-driven fibrosis hypothesis primarily based on bleomycin models of fibrosis, here the same model serves as the basis for Rangarajan et al.’s novel findings on the role of metabolic remodeling in reversing fibrosis. The story is far from over. If there is one lesson that can be learned from the seminal work by Rangarajan et al., it is that careful analysis (and re-analysis) of human pathological lung specimens is how we will learn to understand, diagnose, and treat human pulmonary fibrosis. And, of course, don’t give up an old dog. Dr. Verma has received honoraria and/or research grants from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi." @default.
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• W2891540723 title "Metformin: An Old Dog with a New Trick?" @default.
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