title: A critical role for the mTORC2 pathway in lung fibrosis.
abstract: A characteristic of dysregulated wound healing in IPF is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-β and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in IPF fibroblasts and it mediates the activation by TGF-β of pro-fibrotic pathways. Recent studies show that mTORC2, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking mTORC2 with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and mTORC2, inhibits lung fibrosis. We examined the effect of MLN0128 on TGF-β-mediated induction of stromal proteins in IPF lung fibroblasts; also, we looked at its effect on TGF-β-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-β induces the Rictor component of mTORC2 in IPF lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it (1) inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-β-stimulated IPF fibroblasts; (2) inhibited fibrosis in a murine bleomycin lung model; and (3) protected lung epithelial cells from injury caused by TGF-β-stimulated IPF fibroblasts. Our findings support a role for mTORC2 in the pathogenesis of lung fibrosis and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Wenteh
authors.initials: W
authors.lastname: Chang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Ho
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Berry
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Jacobs
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D001761:Bleomycin; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001583:Benzoxazoles; D001761:Bleomycin; D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; C525637:rictor protein, mouse; C546843:mTOR protein, mouse; C572449:sapanisertib; D000225:Adenine