Skip to main content

Advertisement

SpringerLink
Log in

Role and mechanisms of autophagy in lung metabolism and repair

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Mammalian lungs are metabolically active organs that frequently encounter environmental insults. Stress responses elicit protective autophagy in epithelial barrier cells and the supportive niche. Autophagy promotes the recycling of damaged intracellular organelles, denatured proteins, and other biological macromolecules for reuse as components required for lung cell survival. Autophagy, usually induced by metabolic defects, regulates cellular metabolism. Autophagy is a major adaptive response that protects cells and organisms from injury. Endogenous region-specific stem/progenitor cell populations are found in lung tissue, which are responsible for epithelial repair after lung damage. Additionally, glucose and fatty acid metabolism is altered in lung stem/progenitor cells in response to injury-related lung fibrosis. Autophagy deregulation has been observed to be involved in the development and progression of other respiratory diseases. This review explores the role and mechanisms of autophagy in regulating lung metabolism and epithelial repair.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Liu G, Summer R (2019) Cellular metabolism in lung health and disease. Annu Rev Physiol 81:403–428. https://doi.org/10.1146/annurev-physiol-020518-114640

    Article  CAS  PubMed  Google Scholar 

  2. Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6(4):463–477. https://doi.org/10.1016/s1534-5807(04)00099-1

    Article  CAS  PubMed  Google Scholar 

  3. Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330(6009):1344–1348. https://doi.org/10.1126/science.1193497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kim YC, Guan KL (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 125(1):25–32. https://doi.org/10.1172/JCI73939

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13(9):1016–1023. https://doi.org/10.1038/ncb2329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Neufeld TP (2010) TOR-dependent control of autophagy: biting the hand that feeds. Curr Opin Cell Biol 22(2):157–168. https://doi.org/10.1016/j.ceb.2009.11.005

    Article  CAS  PubMed  Google Scholar 

  7. Agathocleous M, Harris WA (2013) Metabolism in physiological cell proliferation and differentiation. Trends Cell Biol 23(10):484–492. https://doi.org/10.1016/j.tcb.2013.05.004

    Article  CAS  PubMed  Google Scholar 

  8. Aggarwal S, Mannam P, Zhang J (2016) Differential regulation of autophagy and mitophagy in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 311(2):L433-452. https://doi.org/10.1152/ajplung.00128.2016

    Article  PubMed  PubMed Central  Google Scholar 

  9. Nakahira K, Pabon Porras MA, Choi AM (2016) Autophagy in pulmonary diseases. Am J Respir Crit Care Med 194(10):1196–1207. https://doi.org/10.1164/rccm.201512-2468SO

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121(6):823–835. https://doi.org/10.1016/j.cell.2005.03.032

    Article  CAS  PubMed  Google Scholar 

  11. Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y, Vu TH (2011) Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest 121(7):2855–2862. https://doi.org/10.1172/JCI57673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA (2015) Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517(7536):621–625. https://doi.org/10.1038/nature14112

    Article  CAS  PubMed  Google Scholar 

  13. Kumar PA, Hu Y, Yamamoto Y, Hoe NB, Wei TS, Mu D, Sun Y, Joo LS, Dagher R, Zielonka EM, de Wang Y, Lim B, Chow VT, Crum CP, Xian W, McKeon F (2011) Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147(3):525–538. https://doi.org/10.1016/j.cell.2011.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen H, Matsumoto K, Brockway BL, Rackley CR, Liang J, Lee JH, Jiang D, Noble PW, Randell SH, Kim CF, Stripp BR (2012) Airway epithelial progenitors are region specific and show differential responses to bleomycin-induced lung injury. Stem Cells 30(9):1948–1960. https://doi.org/10.1002/stem.1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BL (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123(7):3025–3036. https://doi.org/10.1172/JCI68782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jain R, Barkauskas CE, Takeda N, Bowie EJ, Aghajanian H, Wang Q, Padmanabhan A, Manderfield LJ, Gupta M, Li D, Li L, Trivedi CM, Hogan BLM, Epstein JA (2015) Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat Commun 6:6727. https://doi.org/10.1038/ncomms7727

    Article  CAS  PubMed  Google Scholar 

  17. Wang Y, Tang Z, Huang H, Li J, Wang Z, Yu Y, Zhang C, Li J, Dai H, Wang F, Cai T, Tang N (2018) Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate. Proc Natl Acad Sci USA 115(10):2407–2412. https://doi.org/10.1073/pnas.1719474115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, Niklason L, Calle E, Le A, Randell SH, Rock J, Snitow M, Krummel M, Stripp BR, Vu T, White ES, Whitsett JA, Morrisey EE (2014) Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15(2):123–138. https://doi.org/10.1016/j.stem.2014.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zacharias WJ, Frank DB, Zepp JA, Morley MP, Alkhaleel FA, Kong J, Zhou S, Cantu E, Morrisey EE (2018) Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555(7695):251–255. https://doi.org/10.1038/nature25786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu A, Song H (2020) Regulation of alveolar type 2 stem/progenitor cells in lung injury and regeneration. Acta Biochim Biophys Sin (Shanghai) 52(7):716–722. https://doi.org/10.1093/abbs/gmaa052

    Article  CAS  Google Scholar 

  21. Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24(1):24–41. https://doi.org/10.1038/cr.2013.168

    Article  CAS  PubMed  Google Scholar 

  22. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221(1):3–12. https://doi.org/10.1002/path.2697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kelekar A (2005) Autophagy. Ann N Y Acad Sci 1066:259–271. https://doi.org/10.1196/annals.1363.015

    Article  CAS  PubMed  Google Scholar 

  24. Ohsumi Y (2012) Yoshinori Ohsumi: autophagy from beginning to end. Interview by Caitlin Sedwick. J Cell Biol 197(2):164–165. https://doi.org/10.1083/jcb.1972pi

    Article  PubMed  Google Scholar 

  25. Liao SX, Sun PP, Gu YH, Rao XM, Zhang LY, Ou-Yang Y (2019) Autophagy and pulmonary disease. Ther Adv Respir Dis 13:1753466619890538. https://doi.org/10.1177/1753466619890538

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kim S, Eun HS, Jo EK (2019) Roles of autophagy-related genes in the pathogenesis of inflammatory bowel disease. Cells 8(1):77. https://doi.org/10.3390/cells8010077

    Article  CAS  PubMed Central  Google Scholar 

  27. Morel E, Mehrpour M, Botti J, Dupont N, Hamai A, Nascimbeni AC, Codogno P (2017) Autophagy: a druggable process. Annu Rev Pharmacol Toxicol 57:375–398. https://doi.org/10.1146/annurev-pharmtox-010716-104936

    Article  CAS  PubMed  Google Scholar 

  28. Zhang D, Wang W, Sun X, Xu D, Wang C, Zhang Q, Wang H, Luo W, Chen Y, Chen H, Liu Z (2016) AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy 12(9):1447–1459. https://doi.org/10.1080/15548627.2016.1185576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wesselborg S, Stork B (2015) Autophagy signal transduction by ATG proteins: from hierarchies to networks. Cell Mol Life Sci 72(24):4721–4757. https://doi.org/10.1007/s00018-015-2034-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15(2):81–94. https://doi.org/10.1038/nrm3735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang Z, Klionsky DJ (2009) An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335:1–32. https://doi.org/10.1007/978-3-642-00302-8_1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741. https://doi.org/10.1016/j.cell.2011.10.026

    Article  CAS  PubMed  Google Scholar 

  33. Russell RC, Yuan HX, Guan KL (2014) Autophagy regulation by nutrient signaling. Cell Res 24(1):42–57. https://doi.org/10.1038/cr.2013.166

    Article  CAS  PubMed  Google Scholar 

  34. Goodpaster BH, Sparks LM (2017) Metabolic flexibility in health and disease. Cell Metab 25(5):1027–1036. https://doi.org/10.1016/j.cmet.2017.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bisgrove BW, Yost HJ (2006) The roles of cilia in developmental disorders and disease. Development 133(21):4131–4143. https://doi.org/10.1242/dev.02595

    Article  CAS  PubMed  Google Scholar 

  36. Niethamer TK, Stabler CT, Leach JP, Zepp JA, Morley MP, Babu A, Zhou S, Morrisey EE (2020) Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. Elife. https://doi.org/10.7554/eLife.53072

    Article  PubMed  PubMed Central  Google Scholar 

  37. Remmerie A, Scott CL (2018) Macrophages and lipid metabolism. Cell Immunol 330:27–42. https://doi.org/10.1016/j.cellimm.2018.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Manevski M, Muthumalage T, Devadoss D, Sundar IK, Wang Q, Singh KP, Unwalla HJ, Chand HS, Rahman I (2020) Cellular stress responses and dysfunctional Mitochondrial-cellular senescence, and therapeutics in chronic respiratory diseases. Redox Biol 33:101443. https://doi.org/10.1016/j.redox.2020.101443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, Yang C, Do QN, Doucette S, Burguete D, Li H, Huet G, Yuan Q, Wigal T, Butt Y, Ni M, Torrealba J, Oliver D, Lenkinski RE, Malloy CR, Wachsmann JW, Young JD, Kernstine K, DeBerardinis RJ (2017) Lactate metabolism in human lung tumors. Cell 171(2):358-371.e359. https://doi.org/10.1016/j.cell.2017.09.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Al Hasawi N, Alkandari MF, Luqmani YA (2014) Phosphofructokinase: a mediator of glycolytic flux in cancer progression. Crit Rev Oncol Hematol 92(3):312–321. https://doi.org/10.1016/j.critrevonc.2014.05.007

    Article  PubMed  Google Scholar 

  41. Sreedhar A, Zhao Y (2018) Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells. Biomed Rep 8(1):3–10. https://doi.org/10.3892/br.2017.1022

    Article  CAS  PubMed  Google Scholar 

  42. Stincone A, Prigione A, Cramer T, Wamelink MM, Campbell K, Cheung E, Olin-Sandoval V, Gruning NM, Kruger A, Tauqeer Alam M, Keller MA, Breitenbach M, Brindle KM, Rabinowitz JD, Ralser M (2015) The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc 90(3):927–963. https://doi.org/10.1111/brv.12140

    Article  PubMed  Google Scholar 

  43. Fisher AB, Itakura N, Dodia C, Thurman RG (1981) Pulmonary mixed-function oxidation: stimulation by glucose and the effects of metabolic inhibitors. Biochem Pharmacol 30(4):379–383. https://doi.org/10.1016/0006-2952(81)90070-8

    Article  CAS  PubMed  Google Scholar 

  44. Bassett DJ, Fisher AB (1976) Pentose cycle activity of the isolated perfused rat lung. Am J Physiol 231(5 Pt. 1):1527–1532. https://doi.org/10.1152/ajplegacy.1976.231.5.1527

    Article  CAS  PubMed  Google Scholar 

  45. Ren JG, Seth P, Ye H, Guo K, Hanai JI, Husain Z, Sukhatme VP (2017) Citrate suppresses tumor growth in multiple models through inhibition of glycolysis, the tricarboxylic acid cycle and the IGF-1R pathway. Sci Rep 7(1):4537. https://doi.org/10.1038/s41598-017-04626-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chow LWC, Cheng KS, Leong F, Cheung CW, Shiao LR, Leung YM, Wong KL (2019) Enhancing tetrandrine cytotoxicity in human lung carcinoma A549 cells by suppressing mitochondrial ATP production. Naunyn Schmiedebergs Arch Pharmacol 392(4):427–436. https://doi.org/10.1007/s00210-018-01601-2

    Article  CAS  PubMed  Google Scholar 

  47. Boukhenouna S, Wilson MA, Bahmed K, Kosmider B (2018) Reactive oxygen species in chronic obstructive pulmonary disease. Oxid Med Cell Longev 2018:5730395. https://doi.org/10.1155/2018/5730395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Carracedo A, Cantley LC, Pandolfi PP (2013) Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13(4):227–232. https://doi.org/10.1038/nrc3483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shaw ME, Rhoades RA (1977) Substrate metabolism in the perfused lung: response to changes in circulating glucose and palmitate levels. Lipids 12(11):930–935. https://doi.org/10.1007/BF02533313

    Article  CAS  PubMed  Google Scholar 

  50. Yan F, Wen Z, Wang R, Luo W, Du Y, Wang W, Chen X (2017) Identification of the lipid biomarkers from plasma in idiopathic pulmonary fibrosis by Lipidomics. BMC Pulm Med 17(1):174. https://doi.org/10.1186/s12890-017-0513-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Harayama T, Eto M, Shindou H, Kita Y, Otsubo E, Hishikawa D, Ishii S, Sakimura K, Mishina M, Shimizu T (2014) Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo. Cell Metab 20(2):295–305. https://doi.org/10.1016/j.cmet.2014.05.019

    Article  CAS  PubMed  Google Scholar 

  52. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2(1):9–19. https://doi.org/10.1016/j.cmet.2005.05.009

    Article  CAS  PubMed  Google Scholar 

  53. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13(22):2004–2008. https://doi.org/10.1016/j.cub.2003.10.031

    Article  CAS  PubMed  Google Scholar 

  54. Garcia D, Shaw RJ (2017) AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66(6):789–800. https://doi.org/10.1016/j.molcel.2017.05.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Corhay JL, Henket M, Nguyen D, Duysinx B, Sele J, Louis R (2009) Leukotriene B4 contributes to exhaled breath condensate and sputum neutrophil chemotaxis in COPD. Chest 136(4):1047–1054. https://doi.org/10.1378/chest.08-2782

    Article  CAS  PubMed  Google Scholar 

  56. Kostikas K, Gaga M, Papatheodorou G, Karamanis T, Orphanidou D, Loukides S (2005) Leukotriene B4 in exhaled breath condensate and sputum supernatant in patients with COPD and asthma. Chest 127(5):1553–1559. https://doi.org/10.1378/chest.127.5.1553

    Article  CAS  PubMed  Google Scholar 

  57. Yu Y, Newman H, Shen L, Sharma D, Hu G, Mirando AJ, Zhang H, Knudsen E, Zhang GF, Hilton MJ, Karner CM (2019) Glutamine metabolism regulates proliferation and lineage allocation in skeletal stem cells. Cell Metab 29(4):966-978.e964. https://doi.org/10.1016/j.cmet.2019.01.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ge J, Cui H, Xie N, Banerjee S, Guo S, Dubey S, Barnes S, Liu G (2018) Glutaminolysis promotes collagen translation and stability via alpha-ketoglutarate-mediated mTOR activation and proline hydroxylation. Am J Respir Cell Mol Biol 58(3):378–390. https://doi.org/10.1165/rcmb.2017-0238OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bai L, Bernard K, Tang X, Hu M, Horowitz JC, Thannickal VJ, Sanders YY (2019) Glutaminolysis epigenetically regulates antiapoptotic gene expression in idiopathic pulmonary fibrosis fibroblasts. Am J Respir Cell Mol Biol 60(1):49–57. https://doi.org/10.1165/rcmb.2018-0180OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bernard K, Logsdon NJ, Benavides GA, Sanders Y, Zhang J, Darley-Usmar VM, Thannickal VJ (2018) Glutaminolysis is required for transforming growth factor-beta1-induced myofibroblast differentiation and activation. J Biol Chem 293(4):1218–1228. https://doi.org/10.1074/jbc.RA117.000444

    Article  CAS  PubMed  Google Scholar 

  61. Souba WW, Herskowitz K, Plumley DA (1990) Lung glutamine metabolism. JPEN J Parenter Enter Nutr 14(4 Suppl):68S-70S. https://doi.org/10.1177/014860719001400407

    Article  CAS  Google Scholar 

  62. Pan M, Wasa M, Ryan U, Souba W (1995) Inhibition of pulmonary microvascular endothelial glutamine transport by glucocorticoids and endotoxin. JPEN J Parenter Enter Nutr 19(6):477–481. https://doi.org/10.1177/0148607195019006477

    Article  CAS  Google Scholar 

  63. Labow BI, Abcouwer SF, Lin CM, Souba WW (1998) Glutamine synthetase expression in rat lung is regulated by protein stability. Am J Physiol 275(5):L877-886. https://doi.org/10.1152/ajplung.1998.275.5.L877

    Article  CAS  PubMed  Google Scholar 

  64. Oliveira GP, de Abreu MG, Pelosi P, Rocco PR (2016) Exogenous glutamine in respiratory diseases: myth or reality? Nutrients 8(2):76. https://doi.org/10.3390/nu8020076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mortimore GE, Schworer CM (1977) Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature 270(5633):174–176. https://doi.org/10.1038/270174a0

    Article  CAS  PubMed  Google Scholar 

  66. Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S (2014) Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell 53(4):521–533. https://doi.org/10.1016/j.molcel.2013.12.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Roy S, Leidal AM, Ye J, Ronen SM, Debnath J (2017) Autophagy-dependent shuttling of TBC1D5 controls plasma membrane translocation of GLUT1 and glucose uptake. Mol Cell 67(1):84-95.e85. https://doi.org/10.1016/j.molcel.2017.05.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li K, Li M, Li W, Yu H, Sun X, Zhang Q, Li Y, Li X, Li Y, Abel ED, Wu Q, Chen H (2019) Airway epithelial regeneration requires autophagy and glucose metabolism. Cell Death Dis 10(12):875. https://doi.org/10.1038/s41419-019-2111-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Li X, Wu J, Sun X, Wu Q, Li Y, Li K, Zhang Q, Li Y, Abel ED, Chen H (2020) Autophagy reprograms alveolar progenitor cell metabolism in response to lung injury. Stem Cell Rep 14(3):420–432. https://doi.org/10.1016/j.stemcr.2020.01.008

    Article  CAS  Google Scholar 

  70. Bhatt V, Khayati K, Hu ZS, Lee A, Kamran W, Su X, Guo JY (2019) Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis. Genes Dev 33(3–4):150–165. https://doi.org/10.1101/gad.320481.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Saito T, Kuma A, Sugiura Y, Ichimura Y, Obata M, Kitamura H, Okuda S, Lee HC, Ikeda K, Kanegae Y, Saito I, Auwerx J, Motohashi H, Suematsu M, Soga T, Yokomizo T, Waguri S, Mizushima N, Komatsu M (2019) Autophagy regulates lipid metabolism through selective turnover of NCoR1. Nat Commun 10(1):1567. https://doi.org/10.1038/s41467-019-08829-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Velazquez AP, Tatsuta T, Ghillebert R, Drescher I, Graef M (2016) Lipid droplet-mediated ER homeostasis regulates autophagy and cell survival during starvation. J Cell Biol 212(6):621–631. https://doi.org/10.1083/jcb.201508102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Strohecker AM, White E (2014) Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism. Autophagy 10(2):384–385. https://doi.org/10.4161/auto.27320

    Article  CAS  PubMed  Google Scholar 

  74. Tan HWS, Sim AYL, Long YC (2017) Glutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation. Nat Commun 8(1):338. https://doi.org/10.1038/s41467-017-00369-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Boers JE, Ambergen AW, Thunnissen FB (1998) Number and proliferation of basal and parabasal cells in normal human airway epithelium. Am J Respir Crit Care Med 157(6 Pt 1):2000–2006. https://doi.org/10.1164/ajrccm.157.6.9707011

    Article  CAS  PubMed  Google Scholar 

  76. Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA, Yamamoto Y, Wang X, Lim SJ, Vincent M, Lessard M, Crum CP, Xian W, McKeon F (2015) p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature 517(7536):616–620. https://doi.org/10.1038/nature13903

    Article  CAS  PubMed  Google Scholar 

  77. Daniely Y, Liao G, Dixon D, Linnoila RI, Lori A, Randell SH, Oren M, Jetten AM (2004) Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am J Physiol Cell Physiol 287(1):C171-181. https://doi.org/10.1152/ajpcell.00226.2003

    Article  CAS  PubMed  Google Scholar 

  78. Tadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BL (2014) IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc Natl Acad Sci USA 111(35):E3641-3649. https://doi.org/10.1073/pnas.1409781111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kotton DN, Morrisey EE (2014) Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med 20(8):822–832. https://doi.org/10.1038/nm.3642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Song H, Yao E, Lin C, Gacayan R, Chen MH, Chuang PT (2012) Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci USA 109(43):17531–17536. https://doi.org/10.1073/pnas.1207238109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Snyder JC, Reynolds SD, Hollingsworth JW, Li Z, Kaminski N, Stripp BR (2010) Clara cells attenuate the inflammatory response through regulation of macrophage behavior. Am J Respir Cell Mol Biol 42(2):161–171. https://doi.org/10.1165/rcmb.2008-0353OC

    Article  CAS  PubMed  Google Scholar 

  82. Chen G, Korfhagen TR, Xu Y, Kitzmiller J, Wert SE, Maeda Y, Gregorieff A, Clevers H, Whitsett JA (2009) SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. J Clin Invest 119(10):2914–2924. https://doi.org/10.1172/JCI39731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee JH, Tammela T, Hofree M, Choi J, Marjanovic ND, Han S, Canner D, Wu K, Paschini M, Bhang DH, Jacks T, Regev A, Kim CF (2017) Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell 170(6):1149-1163.e1112. https://doi.org/10.1016/j.cell.2017.07.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Giangreco A, Reynolds SD, Stripp BR (2002) Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol 161(1):173–182. https://doi.org/10.1016/S0002-9440(10)64169-7

    Article  PubMed  PubMed Central  Google Scholar 

  85. Snyder JC, Teisanu RM, Stripp BR (2009) Endogenous lung stem cells and contribution to disease. J Pathol 217(2):254–264. https://doi.org/10.1002/path.2473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rock JR, Hogan BL (2011) Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol 27:493–512. https://doi.org/10.1146/annurev-cellbio-100109-104040

    Article  CAS  PubMed  Google Scholar 

  87. Alder JK, Barkauskas CE, Limjunyawong N, Stanley SE, Kembou F, Tuder RM, Hogan BL, Mitzner W, Armanios M (2015) Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci USA 112(16):5099–5104. https://doi.org/10.1073/pnas.1504780112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Goss V, Hunt AN, Postle AD (2013) Regulation of lung surfactant phospholipid synthesis and metabolism. Biochim Biophys Acta 1831(2):448–458. https://doi.org/10.1016/j.bbalip.2012.11.009

    Article  CAS  PubMed  Google Scholar 

  89. Veith NT, Tschernig T, Gutbier B, Witzenrath M, Meier C, Menger M, Bischoff M (2014) Surfactant protein A mediates pulmonary clearance of Staphylococcusaureus. Respir Res 15:85. https://doi.org/10.1186/s12931-014-0085-2

    Article  PubMed  PubMed Central  Google Scholar 

  90. Glasser SW, Maxfield MD, Ruetschilling TL, Akinbi HT, Baatz JE, Kitzmiller JA, Page K, Xu Y, Bao EL, Korfhagen TR (2013) Persistence of LPS-induced lung inflammation in surfactant protein-C-deficient mice. Am J Respir Cell Mol Biol 49(5):845–854. https://doi.org/10.1165/rcmb.2012-0374OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen F, Krasnow MA (2014) Progenitor outgrowth from the niche in Drosophila trachea is guided by FGF from decaying branches. Science 343(6167):186–189. https://doi.org/10.1126/science.1241442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Desai TJ, Brownfield DG, Krasnow MA (2014) Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507(7491):190–194. https://doi.org/10.1038/nature12930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Peng T, Frank DB, Kadzik RS, Morley MP, Rathi KS, Wang T, Zhou S, Cheng L, Lu MM, Morrisey EE (2015) Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 526(7574):578–582. https://doi.org/10.1038/nature14984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li F, He J, Wei J, Cho WC, Liu X (2015) Diversity of epithelial stem cell types in adult lung. Stem Cells Int 2015:728307. https://doi.org/10.1155/2015/728307

    Article  PubMed  PubMed Central  Google Scholar 

  95. Liu Q, Liu K, Cui G, Huang X, Yao S, Guo W, Qin Z, Li Y, Yang R, Pu W, Zhang L, He L, Zhao H, Yu W, Tang M, Tian X, Cai D, Nie Y, Hu S, Ren T, Qiao Z, Huang H, Zeng YA, Jing N, Peng G, Ji H, Zhou B (2019) Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction. Nat Genet 51(4):728–738. https://doi.org/10.1038/s41588-019-0346-6

    Article  CAS  PubMed  Google Scholar 

  96. Londhe VA, Maisonet TM, Lopez B, Jeng JM, Li C, Minoo P (2011) A subset of epithelial cells with CCSP promoter activity participates in alveolar development. Am J Respir Cell Mol Biol 44(6):804–812. https://doi.org/10.1165/rcmb.2009-0429OC

    Article  CAS  PubMed  Google Scholar 

  97. Gottschling S, Schnabel PA, Herth FJ, Herpel E (2012) Are we missing the target? Cancer stem cells and drug resistance in non-small cell lung cancer. Cancer Genom Proteom 9(5):275–286

    CAS  Google Scholar 

  98. Ferone G, Song JY, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij JP, Proost N, Gargiulo G, Berns A (2016) SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 30(4):519–532. https://doi.org/10.1016/j.ccell.2016.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Liu G, Pei F, Yang F, Li L, Amin AD, Liu S, Buchan JR, Cho WC (2017) Role of autophagy and apoptosis in non-small-cell lung cancer. Int J Mol Sci 18(2):367. https://doi.org/10.3390/ijms18020367

    Article  CAS  PubMed Central  Google Scholar 

  100. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3(12):895–902. https://doi.org/10.1038/nrc1232

    Article  CAS  PubMed  Google Scholar 

  101. Wang J, Li X, Chen H (2020) Organoid models in lung regeneration and cancer. Cancer Lett 475:129–135. https://doi.org/10.1016/j.canlet.2020.01.030

    Article  CAS  PubMed  Google Scholar 

  102. Vanhove K, Derveaux E, Graulus GJ, Mesotten L, Thomeer M, Noben JP, Guedens W, Adriaensens P (2019) Glutamine addiction and therapeutic strategies in lung cancer. Int J Mol Sci 20(2):252. https://doi.org/10.3390/ijms20020252

    Article  CAS  PubMed Central  Google Scholar 

  103. Kimmelman AC, White E (2017) Autophagy and tumor metabolism. Cell Metab 25(5):1037–1043. https://doi.org/10.1016/j.cmet.2017.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hirschhaeuser F, Sattler UG, Mueller-Klieser W (2011) Lactate: a metabolic key player in cancer. Cancer Res 71(22):6921–6925. https://doi.org/10.1158/0008-5472.CAN-11-1457

    Article  CAS  PubMed  Google Scholar 

  105. Mohamed A, Deng X, Khuri FR, Owonikoko TK (2014) Altered glutamine metabolism and therapeutic opportunities for lung cancer. Clin Lung Cancer 15(1):7–15. https://doi.org/10.1016/j.cllc.2013.09.001

    Article  CAS  PubMed  Google Scholar 

  106. Patra KC, Hay N (2014) The pentose phosphate pathway and cancer. Trends Biochem Sci 39(8):347–354. https://doi.org/10.1016/j.tibs.2014.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Merino Salvador M, Gomez de Cedron M, Moreno Rubio J, Falagan Martinez S, Sanchez Martinez R, Casado E, Ramirez de Molina A, Sereno M (2017) Lipid metabolism and lung cancer. Crit Rev Oncol Hematol 112:31–40. https://doi.org/10.1016/j.critrevonc.2017.02.001

    Article  PubMed  Google Scholar 

  108. Gowdy KM, Fessler MB (2013) Emerging roles for cholesterol and lipoproteins in lung disease. Pulm Pharmacol Ther 26(4):430–437. https://doi.org/10.1016/j.pupt.2012.06.002

    Article  CAS  PubMed  Google Scholar 

  109. Kuzu OF, Noory MA, Robertson GP (2016) The role of cholesterol in cancer. Cancer Res 76(8):2063–2070. https://doi.org/10.1158/0008-5472.CAN-15-2613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Xue Y, Han H, Wu L, Pan B, Dong B, Yin CC, Tian Z, Liu X, Yang Y, Zhang H, Chen Y, Chen J (2017) iASPP facilitates tumor growth by promoting mTOR-dependent autophagy in human non-small-cell lung cancer. Cell Death Dis 8(10):e3150. https://doi.org/10.1038/cddis.2017.515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. De Rose V, Molloy K, Gohy S, Pilette C, Greene CM (2018) Airway epithelium dysfunction in cystic fibrosis and COPD. Mediators Inflamm 2018:1309746. https://doi.org/10.1155/2018/1309746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Serre J, Tanjeko AT, Mathyssen C, Vanherwegen AS, Heigl T, Janssen R, Verbeken E, Maes K, Vanaudenaerde B, Janssens W, Gayan-Ramirez G (2021) Enhanced lung inflammatory response in whole-body compared to nose-only cigarette smoke-exposed mice. Respir Res 22(1):86. https://doi.org/10.1186/s12931-021-01680-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Vij N, Chandramani-Shivalingappa P, Van Westphal C, Hole R, Bodas M (2018) Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis. Am J Physiol Cell Physiol 314(1):C73–C87. https://doi.org/10.1152/ajpcell.00110.2016

    Article  CAS  PubMed  Google Scholar 

  114. Chen ZH, Lam HC, Jin Y, Kim HP, Cao J, Lee SJ, Ifedigbo E, Parameswaran H, Ryter SW, Choi AM (2010) Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci USA 107(44):18880–18885. https://doi.org/10.1073/pnas.1005574107

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wang Y, Liu J, Zhou JS, Huang HQ, Li ZY, Xu XC, Lai TW, Hu Y, Zhou HB, Chen HP, Ying SM, Li W, Shen HH, Chen ZH (2018) MTOR suppresses cigarette smoke-induced epithelial cell death and airway inflammation in chronic obstructive pulmonary disease. J Immunol 200(8):2571–2580. https://doi.org/10.4049/jimmunol.1701681

    Article  CAS  PubMed  Google Scholar 

  116. Chen ZH, Kim HP, Sciurba FC, Lee SJ, Feghali-Bostwick C, Stolz DB, Dhir R, Landreneau RJ, Schuchert MJ, Yousem SA, Nakahira K, Pilewski JM, Lee JS, Zhang Y, Ryter SW, Choi AM (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS ONE 3(10):e3316. https://doi.org/10.1371/journal.pone.0003316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Agarwal AR, Zhao L, Sancheti H, Sundar IK, Rahman I, Cadenas E (2012) Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs. Am J Physiol Lung Cell Mol Physiol 303(10):L889-898. https://doi.org/10.1152/ajplung.00219.2012

    Article  CAS  PubMed  Google Scholar 

  118. Dickinson JD, Alevy Y, Malvin NP, Patel KK, Gunsten SP, Holtzman MJ, Stappenbeck TS, Brody SL (2016) IL13 activates autophagy to regulate secretion in airway epithelial cells. Autophagy 12(2):397–409. https://doi.org/10.1080/15548627.2015.1056967

    Article  CAS  PubMed  Google Scholar 

  119. Fujii S, Hara H, Araya J, Takasaka N, Kojima J, Ito S, Minagawa S, Yumino Y, Ishikawa T, Numata T, Kawaishi M, Hirano J, Odaka M, Morikawa T, Nishimura S, Nakayama K, Kuwano K (2012) Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. Oncoimmunology 1(5):630–641. https://doi.org/10.4161/onci.20297

    Article  PubMed  PubMed Central  Google Scholar 

  120. Kikuchi T, Sugiura H, Koarai A, Ichikawa T, Minakata Y, Matsunaga K, Nakanishi M, Hirano T, Akamatsu K, Yanagisawa S, Furukawa K, Kawabata H, Ichinose M (2012) Increase of 27-hydroxycholesterol in the airways of patients with COPD: possible role of 27-hydroxycholesterol in tissue fibrosis. Chest 142(2):329–337. https://doi.org/10.1378/chest.11-2091

    Article  CAS  PubMed  Google Scholar 

  121. Jia J, Conlon TM, Sarker RS, Tasdemir D, Smirnova NF, Srivastava B, Verleden SE, Gunes G, Wu X, Prehn C, Gao J, Heinzelmann K, Lintelmann J, Irmler M, Pfeiffer S, Schloter M, Zimmermann R, Hrabe de Angelis M, Beckers J, Adamski J, Bayram H, Eickelberg O, Yildirim AO (2018) Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease. EMBO Mol Med. https://doi.org/10.15252/emmm.201708349

    Article  PubMed  PubMed Central  Google Scholar 

  122. Beeh KM, Kornmann O, Buhl R, Culpitt SV, Giembycz MA, Barnes PJ (2003) Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest 123(4):1240–1247. https://doi.org/10.1378/chest.123.4.1240

    Article  CAS  PubMed  Google Scholar 

  123. Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZC, Bai Y, Ai X, Lee CH, Zhou X (2017) Genetic control of fatty acid beta-oxidation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 56(6):738–748. https://doi.org/10.1165/rcmb.2016-0282OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Maeyashiki C, Oshima S, Otsubo K, Kobayashi M, Nibe Y, Matsuzawa Y, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Watanabe M (2017) HADHA, the alpha subunit of the mitochondrial trifunctional protein, is involved in long-chain fatty acid-induced autophagy in intestinal epithelial cells. Biochem Biophys Res Commun 484(3):636–641. https://doi.org/10.1016/j.bbrc.2017.01.159

    Article  CAS  PubMed  Google Scholar 

  125. An CH, Wang XM, Lam HC, Ifedigbo E, Washko GR, Ryter SW, Choi AM (2012) TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol 303(9):L748-757. https://doi.org/10.1152/ajplung.00102.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Agarwal AR, Yin F, Cadenas E (2014) Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells. Am J Respir Cell Mol Biol 51(2):284–293. https://doi.org/10.1165/rcmb.2013-0523OC

    Article  CAS  PubMed  Google Scholar 

  127. Zhang Y, Huang W, Zheng Z, Wang W, Yuan Y, Hong Q, Lin J, Li X, Meng Y (2021) Cigarette smoke-inactivated SIRT1 promotes autophagy-dependent senescence of alveolar epithelial type 2 cells to induce pulmonary fibrosis. Free Radic Biol Med 166:116–127. https://doi.org/10.1016/j.freeradbiomed.2021.02.013

    Article  CAS  PubMed  Google Scholar 

  128. Yu Y, Li W, Ren L, Yang C, Li D, Han X, Sun Y, Lv C, Han F (2018) Inhibition of autophagy enhanced cobalt chlorideinduced apoptosis in rat alveolar type II epithelial cells. Mol Med Rep 18(2):2124–2132. https://doi.org/10.3892/mmr.2018.9209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM (2005) Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med 11(5):491–498. https://doi.org/10.1038/nm1238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Tsutsumi A, Ozaki M, Chubachi S, Irie H, Sato M, Kameyama N, Sasaki M, Ishii M, Hegab AE, Betsuyaku T, Fukunaga K (2020) Exposure to cigarette smoke enhances the stemness of alveolar type 2 cells. Am J Respir Cell Mol Biol 63(3):293–305. https://doi.org/10.1165/rcmb.2019-0188OC

    Article  CAS  PubMed  Google Scholar 

  131. Holgate ST (2008) The airway epithelium is central to the pathogenesis of asthma. Allergol Int 57(1):1–10. https://doi.org/10.2332/allergolint.R-07-154

    Article  CAS  PubMed  Google Scholar 

  132. Papi A, Brightling C, Pedersen SE, Reddel HK (2018) Asthma. Lancet 391(10122):783–800. https://doi.org/10.1016/S0140-6736(17)33311-1

    Article  PubMed  Google Scholar 

  133. Farooq MB, Walsh GM (2016) Autophagy and asthma. Clin Exp Allergy 46(1):7–9. https://doi.org/10.1111/cea.12633

    Article  CAS  PubMed  Google Scholar 

  134. Ban GY, Pham DL, Trinh TH, Lee SI, Suh DH, Yang EM, Ye YM, Shin YS, Chwae YJ, Park HS (2016) Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target. Clin Exp Allergy 46(1):48–59. https://doi.org/10.1111/cea.12585

    Article  CAS  PubMed  Google Scholar 

  135. Qian X, Aboushousha R, van de Wetering C, Chia SB, Amiel E, Schneider RW, van der Velden JLJ, Lahue KG, Hoagland DA, Casey DT, Daphtary N, Ather JL, Randall MJ, Aliyeva M, Black KE, Chapman DG, Lundblad LKA, McMillan DH, Dixon AE, Anathy V, Irvin CG, Poynter ME, Wouters EFM, Vacek PM, Henket M, Schleich F, Louis R, van der Vliet A, Janssen-Heininger YMW (2018) IL-1/inhibitory kappaB kinase epsilon-induced glycolysis augment epithelial effector function and promote allergic airways disease. J Allergy Clin Immunol 142(2):435-450.e410. https://doi.org/10.1016/j.jaci.2017.08.043

    Article  CAS  PubMed  Google Scholar 

  136. Casalino-Matsuda SM, Monzon ME, Forteza RM (2006) Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am J Respir Cell Mol Biol 34(5):581–591. https://doi.org/10.1165/rcmb.2005-0386OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ko HM, Kang NI, Kim YS, Lee YM, Jin ZW, Jung YJ, Im SY, Kim JH, Shin YH, Cho BH, Lee HK (2008) Glutamine preferentially inhibits T-helper type 2 cell-mediated airway inflammation and late airway hyperresponsiveness through the inhibition of cytosolic phospholipase A(2) activity in a murine asthma model. Clin Exp Allergy 38(2):357–364. https://doi.org/10.1111/j.1365-2222.2007.02900.x

    Article  CAS  PubMed  Google Scholar 

  138. Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I (2009) Mitochondrial dysfunction increases allergic airway inflammation. J Immunol 183(8):5379–5387. https://doi.org/10.4049/jimmunol.0900228

    Article  CAS  PubMed  Google Scholar 

  139. Matsunaga K, Kuwahira I, Hanaoka M, Saito J, Tsuburai T, Fukunaga K, Matsumoto H, Sugiura H, Ichinose M, Japanese Respiratory Society Assembly on Pulmonary P (2021) An official JRS statement: the principles of fractional exhaled nitric oxide (FeNO) measurement and interpretation of the results in clinical practice. Respir Investig 59(1):34–52. https://doi.org/10.1016/j.resinv.2020.05.006

    Article  PubMed  Google Scholar 

  140. Yates DH (2001) Role of exhaled nitric oxide in asthma. Immunol Cell Biol 79(2):178–190. https://doi.org/10.1046/j.1440-1711.2001.00990.x

    Article  CAS  PubMed  Google Scholar 

  141. Ghisalberti CA, Borzi RM, Cetrullo S, Flamigni F, Cairo G (2016) Soft TCPTP agonism-novel target to rescue airway epithelial integrity by exogenous spermidine. Front Pharmacol 7:147. https://doi.org/10.3389/fphar.2016.00147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Barrios J, Kho AT, Aven L, Mitchel JA, Park JA, Randell SH, Miller LA, Tantisira KG, Ai X (2019) Pulmonary neuroendocrine cells secrete gamma-aminobutyric acid to induce goblet cell hyperplasia in primate models. Am J Respir Cell Mol Biol 60(6):687–694. https://doi.org/10.1165/rcmb.2018-0179OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, Rosas IO, Morse D (2012) Autophagy in idiopathic pulmonary fibrosis. PLoS ONE 7(7):e41394. https://doi.org/10.1371/journal.pone.0041394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lv X, Li K, Hu Z (2020) Autophagy and pulmonary fibrosis. Adv Exp Med Biol 1207:569–579. https://doi.org/10.1007/978-981-15-4272-5_40

    Article  CAS  PubMed  Google Scholar 

  146. Richeldi L, Collard HR, Jones MG (2017) Idiopathic pulmonary fibrosis. Lancet 389(10082):1941–1952. https://doi.org/10.1016/S0140-6736(17)30866-8

    Article  PubMed  Google Scholar 

  147. Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, Yanagisawa H, Kobayashi K, Tsurushige C, Kawaishi M, Kamiya N, Hirano J, Odaka M, Morikawa T, Nishimura SL, Kawabata Y, Hano H, Nakayama K, Kuwano K (2013) Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 304(1):L56-69. https://doi.org/10.1152/ajplung.00213.2012

    Article  CAS  PubMed  Google Scholar 

  148. Cabrera S, Maciel M, Herrera I, Nava T, Vergara F, Gaxiola M, Lopez-Otin C, Selman M, Pardo A (2015) Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis. Autophagy 11(4):670–684. https://doi.org/10.1080/15548627.2015.1034409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mi S, Li Z, Yang HZ, Liu H, Wang JP, Ma YG, Wang XX, Liu HZ, Sun W, Hu ZW (2011) Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J Immunol 187(6):3003–3014. https://doi.org/10.4049/jimmunol.1004081

    Article  CAS  PubMed  Google Scholar 

  150. Yang HZ, Wang JP, Mi S, Liu HZ, Cui B, Yan HM, Yan J, Li Z, Liu H, Hua F, Lu W, Hu ZW (2012) TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury. Am J Pathol 180(1):275–292. https://doi.org/10.1016/j.ajpath.2011.09.019

    Article  CAS  PubMed  Google Scholar 

  151. Tanjore H, Cheng DS, Degryse AL, Zoz DF, Abdolrasulnia R, Lawson WE, Blackwell TS (2011) Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J Biol Chem 286(35):30972–30980. https://doi.org/10.1074/jbc.M110.181164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kliment CR, Oury TD (2010) Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Free Radic Biol Med 49(5):707–717. https://doi.org/10.1016/j.freeradbiomed.2010.04.036

    Article  CAS  PubMed  Google Scholar 

  153. Tzouvelekis A, Harokopos V, Paparountas T, Oikonomou N, Chatziioannou A, Vilaras G, Tsiambas E, Karameris A, Bouros D, Aidinis V (2007) Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. Am J Respir Crit Care Med 176(11):1108–1119. https://doi.org/10.1164/rccm.200705-683OC

    Article  PubMed  Google Scholar 

  154. Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281(40):30299–30304. https://doi.org/10.1074/jbc.M607007200

    Article  CAS  PubMed  Google Scholar 

  155. Gao Q (2019) Oxidative stress and autophagy. Adv Exp Med Biol 1206:179–198. https://doi.org/10.1007/978-981-15-0602-4_9

    Article  CAS  PubMed  Google Scholar 

  156. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283(16):10892–10903. https://doi.org/10.1074/jbc.M800102200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kang YP, Lee SB, Lee JM, Kim HM, Hong JY, Lee WJ, Choi CW, Shin HK, Kim DJ, Koh ES, Park CS, Kwon SW, Park SW (2016) Metabolic profiling regarding pathogenesis of idiopathic pulmonary fibrosis. J Proteome Res 15(5):1717–1724. https://doi.org/10.1021/acs.jproteome.6b00156

    Article  CAS  PubMed  Google Scholar 

  158. Zhao YD, Yin L, Archer S, Lu C, Zhao G, Yao Y, Wu L, Hsin M, Waddell TK, Keshavjee S, Granton J, de Perrot M (2017) Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study. BMJ Open Respir Res 4(1):e000183. https://doi.org/10.1136/bmjresp-2017-000183

    Article  PubMed  PubMed Central  Google Scholar 

  159. Somborac-Bacura A, Rumora L, Novak R, Rasic D, Dumic J, Cepelak I, Zanic-Grubisic T (2018) Differential expression of heat shock proteins and activation of mitogen-activated protein kinases in A549 alveolar epithelial cells exposed to cigarette smoke extract. Exp Physiol 103(12):1666–1678. https://doi.org/10.1113/EP087038

    Article  CAS  PubMed  Google Scholar 

  160. Yao M, Wang X, Tang Y, Zhang W, Cui B, Liu Q, Xing L (2014) Dicer mediating the expression of miR-143 and miR-155 regulates hexokinase II associated cellular response to hypoxia. Am J Physiol Lung Cell Mol Physiol 307(11):L829-837. https://doi.org/10.1152/ajplung.00081.2014

    Article  CAS  PubMed  Google Scholar 

  161. Zhao H, Dennery PA, Yao H (2018) Metabolic reprogramming in the pathogenesis of chronic lung diseases, including BPD, COPD, and pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 314(4):L544–L554. https://doi.org/10.1152/ajplung.00521.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shyh-Chang N, Ng HH (2017) The metabolic programming of stem cells. Genes Dev 31(4):336–346. https://doi.org/10.1101/gad.293167.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464. https://doi.org/10.1146/annurev-cellbio-092910-154237

    Article  CAS  PubMed  Google Scholar 

  164. Hu C, Fan L, Cen P, Chen E, Jiang Z, Li L (2016) Energy metabolism plays a critical role in stem cell maintenance and differentiation. Int J Mol Sci 17(2):253. https://doi.org/10.3390/ijms17020253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Cantin AM, Hubbard RC, Crystal RG (1989) Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 139(2):370–372. https://doi.org/10.1164/ajrccm/139.2.370

    Article  CAS  PubMed  Google Scholar 

  166. Galluzzi L, Pietrocola F, Levine B, Kroemer G (2014) Metabolic control of autophagy. Cell 159(6):1263–1276. https://doi.org/10.1016/j.cell.2014.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Dupont N, Chauhan S, Arko-Mensah J, Castillo EF, Masedunskas A, Weigert R, Robenek H, Proikas-Cezanne T, Deretic V (2014) Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr Biol 24(6):609–620. https://doi.org/10.1016/j.cub.2014.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chu SG, Villalba JA, Liang X, Xiong K, Tsoyi K, Ith B, Ayaub EA, Tatituri RV, Byers DE, Hsu FF, El-Chemaly S, Kim EY, Shi Y, Rosas IO (2019) Palmitic acid-rich high-fat diet exacerbates experimental pulmonary fibrosis by modulating endoplasmic reticulum stress. Am J Respir Cell Mol Biol 61(6):737–746. https://doi.org/10.1165/rcmb.2018-0324OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Suryadevara V, Ramchandran R, Kamp DW, Natarajan V (2020) Lipid mediators regulate pulmonary fibrosis: potential mechanisms and signaling pathways. Int J Mol Sci 21(12):4257. https://doi.org/10.3390/ijms21124257

    Article  CAS  PubMed Central  Google Scholar 

  170. Bueno M, Lai YC, Romero Y, Brands J, St Croix CM, Kamga C, Corey C, Herazo-Maya JD, Sembrat J, Lee JS, Duncan SR, Rojas M, Shiva S, Chu CT, Mora AL (2015) PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest 125(2):521–538. https://doi.org/10.1172/JCI74942

    Article  PubMed  Google Scholar 

  171. Galluzzi L, Kepp O, Kroemer G (2012) Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol 13(12):780–788. https://doi.org/10.1038/nrm3479

    Article  CAS  PubMed  Google Scholar 

  172. Chung KP, Hsu CL, Fan LC, Huang Z, Bhatia D, Chen YJ, Hisata S, Cho SJ, Nakahira K, Imamura M, Choi ME, Yu CJ, Cloonan SM, Choi AMK (2019) Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis. Nat Commun 10(1):3390. https://doi.org/10.1038/s41467-019-11327-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (81773394, 81970001, 82070001), Natural Science Foundation of Tianjin (20JCQNJC01790, 18ZXDBSY00150) and Science and Technology Planning Project of Tianjin Jinnan District (20200118).

Author information

Authors and Affiliations

  1. Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China

    Xue Li, Peiyong Cheng & Huaiyong Chen

  2. Department of Basic Medicine, Haihe Clinical College of Tianjin Medical University, Tianjin, China

    Fuxiaonan Zhao, An Wang & Huaiyong Chen

  3. Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China

    Huaiyong Chen

  4. Tianjin Key Laboratory of Lung Regenerative Medicine, Haihe Hospital, Tianjin University, Tianjin, China

    Huaiyong Chen

Authors
  1. Xue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fuxiaonan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. An Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peiyong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huaiyong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huaiyong Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., Zhao, F., Wang, A. et al. Role and mechanisms of autophagy in lung metabolism and repair. Cell. Mol. Life Sci. 78, 5051–5068 (2021). https://doi.org/10.1007/s00018-021-03841-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-021-03841-7

Keywords

Search

Navigation