This is a preview and has not been published.

Landscape analysis and overview of the literature on oxidative stress and pulmonary diseases


  • Xin Liu a:1:s:5:"en_US":s:11:"18830180711":
  • Xiaofan Wang
  • Jing Chang
  • Hongmin Zhang
  • Pengxiu Cao


oxidative stress, inflammation, mitochondria, antioxidants, pulmonary disease


Oxidative stress is caused by an imbalance in the oxidant/anti-oxidant processes and it is critical factor participating in pulmonary diseases. As no truly effective therapies exist for lung cancer, lung fibrosis and chronic obstructive pulmonary disease (COPD), at present, it is important for us to study the full relation of oxidative stress and pulmonary diseases for truly effective therapeutics. Since there is no quantitative and qualitative bibliometrics analysis of the literature in this area, this review provides an in-depth analysis on the publications related to oxidative stress and pulmonary diseases over five periods, from 1950 to 2020, 1950 to 2005, 2006 to 2010, 2011 to 2015, and 2016 to 2020. The pulmonary diseases with rising interests, mechanisms and therapeutic drugs on pulmonary diseases were well analyzed. Lung cancer, lung injury, lung fibrosis, asthma and COPD are 5 most studied pulmonary diseases related to oxidative stress. Inflammation, apoptosis, and nuclear factor erythroid 2 like 2 (NRF2), autophagy, mitochondria, nuclear factor-κB (NF-κB) are the top six author keywords with the fastest rising speed. Three antioxidants, vitamin E (tocopherol), N-acetylcysteine, curcumin and another 22 drugs of potential therapeutics were summarized. Instead of as one single "magic bullet", antioxidants, especially targeting reactive oxygen species (ROS) in specific organelles and a certain disease may be a substantial and necessary choice in combined therapies for the effective treatment of refractory pulmonary diseases.


Download data is not yet available.



Hebei Normal University, Shijiazhuang, Hebei, China.

Xiaofan Wang

Hebei Normal University, Shijiazhuang, Hebei, China.

Pengxiu Cao

Hebei Normal University, Shijiazhuang, Hebei, China.Professer


Klaunig, J.E. Oxidative Stress and Cancer. Curr. Pharm. Des. 2018, 24, 4771-4778.

Steven, S.; Frenis, K.; Oelze, M.; Kalinovic, S.; Kuntic, M.; Bayo Jimenez, M.T.; Vujacic-Mirski, K.; Helmstädter, J.; Kröller-Schön, S.; Münzel, T.; Daiber, A. Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease. Oxidative Medicine and Cellular Longevity 2019, 2019, 1-26.

Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules 2019, 24, 1583.

van der Vliet, A.; Janssen-Heininger, Y.M.W.; Anathy, V. Oxidative stress in chronic lung disease: From mitochondrial dysfunction to dysregulated redox signaling. Mol. Aspects Med. 2018, 63, 59-69.

Uchiyama, N.; Yukawa, T.; Dragan, Y.P.; Wagoner, M.P.; Naven, R.T. New phenotypic cytotoxicity assay for ROS-inducing compounds using rat renal epithelial cells. Toxicol. Lett. 2020, 331, 227-234.

Owusu, S.B.; Hudik, E.; Ferard, C.; Dupre-Crochet, S.; Addison, E.; Preko, K.; Bizouarn, T.; Houee-Levin, C.; Baciou, L. Radiation-induced reactive oxygen species partially assemble neutrophil NADPH oxidase. Free radical biology & medicine 2020, 164, 76-84.

Helmig, S.; Walter, D.; Putzier, J.; Maxeiner, H.; Wenzel, S.; Schneider, J. Oxidative and cytotoxic stress induced by inorganic granular and fibrous particles. Molecular medicine reports 2018, 17, 8518-8529.

Tostes, R.C.; Carneiro, F.S.; Lee, A.J.; Giachini, F.R.; Leite, R.; Osawa, Y.; Webb, R. C. Cigarette smoking and erectile dysfunction: focus on NO bioavailability and ROS generation. J Sex Med 2008, 5, 1284-1295.

Dan Dunn, J.; Alvarez, L.A.; Zhang, X.; Soldati, T. Reactive oxygen species and mitochondria: A nexus of cellular homeostasis. Redox biology 2015, 6, 472-485.

Forrester, S.J.; Kikuchi, D.S.; Hernandes, M.S.; Xu, Q.; Griendling, K.K. Reactive Oxygen Species in Metabolic and Inflammatory Signaling. Circ. Res. 2018, 122, 877-902.

Martinez, M.C.; Andriantsitohaina, R. Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid. Redox Signal. 2009, 11, 669-702.

Margis, R.; Dunand, C.; Teixeira, F.K.; Margis-Pinheiro, M. Glutathione peroxidase family - an evolutionary overview. FEBS J. 2008, 275, 3959-3970.

Chatterjee, A.; Gupta, S. The multifaceted role of glutathione S-transferases in cancer. Cancer Lett. 2018, 433, 33-42.

Weydert, C.J.; Cullen, J.J. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nature Protocols 2009, 5, 51-66.

Schmitt, B.; Vicenzi, M.; Garrel, C.; Denis, F.M. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox biology 2015, 6, 198-205.

Lee, G.Y.; Han, S.N. The Role of Vitamin E in Immunity. Nutrients 2018, 10, 1614.

Pizzino, G.; Irrera, N.; Cucinotta, M.; Pallio, G.; Mannino, F.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Oxidative Stress: Harms and Benefits for Human Health. Oxidative Medicine and Cellular Longevity 2017, 2017, 1-13.

Cheresh, P.; Kim, S.J.; Tulasiram, S.; Kamp, D.W. Oxidative stress and pulmonary fibrosis. Biochim. Biophys. Acta 2013, 1832, 1028-1040.

Wiegman, C.H.; Li, F.; Ryffel, B.; Togbe, D.; Chung, K.F. Oxidative Stress in Ozone-Induced Chronic Lung Inflammation and Emphysema: A Facet of Chronic Obstructive Pulmonary Disease. Front Immunol. 2020, 11, 1957.

Duecker, R.; Baer, P.; Eickmeier, O.; Strecker, M.; Kurz, J.; Schaible, A.; Henrich, D.; Zielen, S.; Schubert, R. Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia. Redox biology 2018, 14, 645-655.

Ghio, A.J.; Carter, J.D.; Richards, J.H.; Richer, L.D.; Grissom, C.K.; Elstad, M.R. Iron and iron-related proteins in the lower respiratory tract of patients with acute respiratory distress syndrome. Crit. Care Med. 2003, 31, 395-400.

Reid, D.W.; Carroll, V.; O'May, C.; Champion, A.; Kirov, S.M. Increased airway iron as a potential factor in the persistence of Pseudomonas aeruginosa infection in cystic fibrosis. Eur. Respir. J. 2007, 30, 286-292.

Philippot, Q.; Deslee, G.; Adair-Kirk, T.L.; Woods, J.C.; Byers, D.; Conradi, S.; Dury, S.; Perotin, J.M.; Lebargy, F.; Cassan, C.; Le Naour, R.; Holtzman, M.J.; Pierce, R.A. Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. PLoS One 2014, 9, e96285.

Yu, G.; Tzouvelekis, A.; Wang, R.; Herazo-Maya, J.D.; Ibarra, G.H.; Srivastava, A.; de Castro, J.P.W.; DeIuliis, G.; Ahangari, F.; Woolard, T.; Aurelien, N.; Arrojo, E.D.R.; Gan, Y.; Graham, M.; Liu, X.; Homer, R.J.; Scanlan, T.S.; Mannam, P.; Lee, P.J.; Herzog, E.L.; Bianco, A.C.; Kaminski, N. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat. Med. 2018, 24, 39-49.

Rangarajan, S.; Bone, N.B.; Zmijewska, A.A.; Jiang, S.; Park, D.W.; Bernard, K.; Locy, M.L.; Ravi, S.; Deshane, J.; Mannon, R.B.; Abraham, E.; Darley-Usmar, V.; Thannickal, V.J.; Zmijewski, J.W. Metformin reverses established lung fibrosis in a bleomycin model. Nat. Med. 2018, 24, 1121-1127.

Kirkham, P.A.; Barnes, P.J. Oxidative stress in COPD. Chest 2013, 144, 266-273.

Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: how are they linked? Free radical biology & medicine 2010, 49, 1603-1616.

Hussain, T.; Tan, B.; Yin, Y.; Blachier, F.; Tossou, M.C.; Rahu, N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid. Med. Cell Longev. 2016, 2016, 7432797.

Mokhtari-Zaer, A.; Norouzi, F.; Askari, V.R.; Khazdair, M.R.; Roshan, N.M.; Boskabady, M.; Hosseini, M.; Boskabady, M.H. The protective effect of Nigella sativa extract on lung inflammation and oxidative stress induced by lipopolysaccharide in rats. J. Ethnopharmacol. 2020, 253, 112653.

Flohe, L.; Brigelius-Flohe, R.; Saliou, C.; Traber, M.G.; Packer, L. Redox regulation of NF-kappa B activation. Free radical biology & medicine 1997, 22, 1115-1126.

Liu, X.; Chen, Z. The pathophysiological role of mitochondrial oxidative stress in lung diseases. J. Transl. Med. 2017, 15, 207.

Wiegman, C.H.; Michaeloudes, C.; Haji, G.; Narang, P.; Clarke, C.J.; Russell, K.E.; Bao, W.; Pavlidis, S.; Barnes, P.J.; Kanerva, J.; Bittner, A.; Rao, N.; Murphy, M.P.; Kirkham, P.A.; Chung, K.F.; Adcock, I.M.; Brightling, C.E.; Davies, D.E.; Finch, D.K.; Fisher, A.J.; Gaw, A.; Knox, A.J.; Mayer, R.J.; Polkey, M.; Salmon, M.; Singh, D. Oxidative stress–induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2015, 136, 769-780.

Neves, J.; Haider, T.; Gassmann, M.; Muckenthaler, M.U. Iron Homeostasis in the Lungs-A Balance between Health and Disease. Pharmaceuticals (Basel) 2019, 12, 5.

Ghio, A.J.; Stonehuerner, J.G.; Richards, J.H.; Crissman, K.M.; Roggli, V.L.; Piantadosi, C.A.; Carraway, M. S. Iron homeostasis and oxidative stress in idiopathic pulmonary alveolar proteinosis: a case-control study. Respir. Res. 2008, 9, 10.

Ali, M.K.; Kim, R.Y.; Brown, A.C.; Donovan, C.; Vanka, K.S.; Mayall, J. R.; Liu, G.; Pillar, A.L.; Jones-Freeman, B.; Xenaki, D.; Borghuis, T.; Karim, R.; Pinkerton, J.W.; Aryal, R.; Heidari, M.; Martin, K.L.; Burgess, J.K.; Oliver, B.G.; Trinder, D.; Johnstone, D.M.; Milward, E.A.; Hansbro, P.M.; Horvat, J.C. Critical role for iron accumulation in the pathogenesis of fibrotic lung disease. J. Pathol. 2020, 251, 49-62.

Lu, C.; Koppenol, W.H. Inhibition of the Fenton reaction by nitrogen monoxide. J. Biol. Inorg. Chem. 2005, 10, 732-738.

Gu, L.; Larson Casey, J.L.; Andrabi, S.A.; Lee, J.H.; Meza-Perez, S.; Randall, T.D.; Carter, A.B. Mitochondrial calcium uniporter regulates PGC-1alpha expression to mediate metabolic reprogramming in pulmonary fibrosis. Redox biology 2019, 26, 101307.

Wang, H.; Liu, C.; Zhao, Y.; Gao, G. Mitochondria regulation in ferroptosis. Eur. J. Cell Biol. 2020, 99, 151058.

Seibt, T.M.; Proneth, B.; Conrad, M. Role of GPX4 in ferroptosis and its pharmacological implication. Free radical biology & medicine 2019, 133, 144-152.

Yoshida, M.; Minagawa, S.; Araya, J.; Sakamoto, T.; Hara, H.; Tsubouchi, K.; Hosaka, Y.; Ichikawa, A.; Saito, N.; Kadota, T.; Sato, N.; Kurita, Y.; Kobayashi, K.; Ito, S.; Utsumi, H.; Wakui, H.; Numata, T.; Kaneko, Y.; Mori, S.; Asano, H.; Yamashita, M.; Odaka, M.; Morikawa, T.; Nakayama, K.; Iwamoto, T.; Imai, H.; Kuwano, K. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nat. Commun. 2019, 10, 3145.

Li, X.; Zhuang, X.; Qiao, T. Role of ferroptosis in the process of acute radiation-induced lung injury in mice. Biochem. Biophys. Res. Commun. 2019, 519, 240-245.

Liu, P.; Feng, Y.; Li, H.; Chen, X.; Wang, G.; Xu, S.; Li, Y.; Zhao, L. Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis. Cell. Mol. Biol. Lett. 2020, 25, 10.

Alvarez, S.W.; Sviderskiy, V.O.; Terzi, E.M.; Papagiannakopoulos, T.; Moreira, A.L.; Adams, S.; Sabatini, D.M.; Birsoy, K.; Possemato, R. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 2017, 551, 639-643.

Sachdeva, K.; Do, D.C.; Zhang, Y.; Hu, X.; Chen, J.; Gao, P. Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence. Front Immunol. 2019, 10, 2787.

Prashanth Goud, M.; Bale, S.; Pulivendala, G.; Godugu, C. Therapeutic effects of Nimbolide, an autophagy regulator, in ameliorating pulmonary fibrosis through attenuation of TGF-beta1 driven epithelial-to-mesenchymal transition. Int. Immunopharmacol. 2019, 75, 105755.

Chen, A.C.; Burr, L.; McGuckin, M.A. Oxidative and endoplasmic reticulum stress in respiratory disease. Clinical & translational immunology 2018, 7, e1019.

Tuleta, I.; Stockigt, F.; Juergens, U.R.; Pizarro, C.; Schrickel, J.W.; Kristiansen, G.; Nickenig, G.; Skowasch, D. Intermittent Hypoxia Contributes to the Lung Damage by Increased Oxidative Stress, Inflammation, and Disbalance in Protease/Antiprotease System. Lung 2016, 194, 1015-1020.

Fan, J.; Lv, H.; Li, J.; Che, Y.; Xu, B.; Tao, Z.; Jiang, W. Roles of Nrf2/HO-1 and HIF-1alpha/VEGF in lung tissue injury and repair following cerebral ischemia/reperfusion injury. J. Cell. Physiol. 2019, 234, 7695-7707.

Itoh, K.; Ishii, T.; Wakabayashi, N.; Yamamoto, M. Regulatory mechanisms of cellular response to oxidative stress. Free radical research 1999, 31, 319-324.

Martin, F.; van Deursen, J.M.; Shivdasani, R.A.; Jackson, C.W.; Troutman, A.G.; Ney, P.A. Erythroid maturation and globin gene expression in mice with combined deficiency of NF-E2 and nrf-2. Blood 1998, 91, 3459-3466.

Hybertson, B.M.; Gao, B.; Bose, S.K.; McCord, J. M. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol. Aspects Med. 2011, 32, 234-246.

Singh, A.; Misra, V.; Thimmulappa, R.K.; Lee, H.; Ames, S.; Hoque, M.O.; Herman, J.G.; Baylin, S.B.; Sidransky, D.; Gabrielson, E.; Brock, M.V.; Biswal, S. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006, 3, e420.

Tian, Y.; Liu, Q.; Yu, S.; Chu, Q.; Chen, Y.; Wu, K.; Wang, L. NRF2-Driven KEAP1 Transcription in Human Lung Cancer. Mol. Cancer Res. 2020, 18, 1465-1476.

Bellezza, I.; Giambanco, I.; Minelli, A.; Donato, R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim. Biophys. Acta Mol. Cell Res. 2018, 1865, 721-733.

Huang, C.Y.; Deng, J.S.; Huang, W.C.; Jiang, W.P.; Huang, G.J. Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy. Nutrients 2020, 12, 1742.

Zhou, W.; Mo, X.; Cui, W.; Zhang, Z.; Li, D.; Li, L.; Xu, L.; Yao, H.; Gao, J. Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis. Scientific Reports 2016, 6, 38646.

Dong, H.; Qiang, Z.; Chai, D.; Peng, J.; Xia, Y.; Hu, R.; Jiang, H. Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1. Aging 2020, 12, 12943-12959.

Zhou, W.; Mo, X.; Cui, W.; Zhang, Z.; Li, D.; Li, L.; Xu, L.; Yao, H.; Gao, J. Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis. Sci. Rep. 2016, 6, 38646.

Zhang, Z.; Qu, J.; Zheng, C.; Zhang, P.; Zhou, W.; Cui, W.; Mo, X.; Li, L.; Xu, L.; Gao, J. Nrf2 antioxidant pathway suppresses Numb-mediated epithelial-mesenchymal transition during pulmonary fibrosis. Cell death & disease 2018, 9, 83.

Dianat, M.; Radan, M.; Badavi, M.; Mard, S.A.; Bayati, V.; Ahmadizadeh, M. Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of Nrf2 antioxidant system in preventing oxidative stress. Respir. Res. 2018, 19, 58.

Lu, M. C.; Ji, J.A.; Jiang, Z.Y.; You, Q.D. The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update. Medicinal research reviews 2016, 36, 924-963.

Bahn, G.; Jo, D.G. Therapeutic Approaches to Alzheimer's Disease Through Modulation of NRF2. Neuromolecular Med. 2019, 21, 1-11.

Ge, ZD.; Lian, Q.; Mao, X.; Xia, Z. Current Status and Challenges of NRF2 as a Potential Therapeutic Target for Diabetic Cardiomyopathy. International heart journal 2019, 60, 512-520.

Zhou, L.; Liu, Y.; Chen, X.; Wang, S.; Liu, H.; Zhang, T.; Zhang, Y.; Xu, Q.; Han, X.; Zhao, Y.; Song, X.; Ye, L. Over-expression of nuclear factor-kappaB family genes and inflammatory molecules is related to chronic obstructive pulmonary disease. International journal of chronic obstructive pulmonary disease 2018, 13, 2131-2138.

Goldkorn, T.; Filosto, S.; Chung, S. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor. Antioxid. Redox Signal. 2014, 21, 2149-2174.

Barnes, P.J. Cellular and molecular mechanisms of asthma and COPD. Clinical science 2017, 131, 1541-1558.

Lewis, E.D.; Meydani, S. N.; Wu, D. Regulatory role of vitamin E in the immune system and inflammation. IUBMB life 2019, 71, 487-494.

Raghu, G.; Berk, M.; Campochiaro, P.A.; Jaeschke, H.; Marenzi, G.; Richeldi, L.; Wen, F.Q.; Nicoletti, F.; Calverley, P.M.A. The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress. Current neuropharmacology 2020, doi: 10.2174/1570159X19666201230144109.

Impellizzeri, D.; Talero, E.; Siracusa, R.; Alcaide, A.; Cordaro, M.; Maria Zubelia, J.; Bruschetta, G.; Crupi, R.; Esposito, E.; Cuzzocrea, S.; Motilva, V. Protective effect of polyphenols in an inflammatory process associated with experimental pulmonary fibrosis in mice. The British journal of nutrition 2015, 114, 853-865.

Conte, E.; Fagone, E.; Fruciano, M.; Gili, E.; Iemmolo, M.; Vancheri, C. Anti-inflammatory and antifibrotic effects of resveratrol in the lung. Histology and histopathology 2015, 30, 523-529.

Amini, P.; Saffar, H.; Nourani, M.R.; Motevaseli, E.; Najafi, M.; Ali Taheri, R.; Qazvini, A. Curcumin Mitigates Radiation-induced Lung Pneumonitis and Fibrosis in Rats. International journal of molecular and cellular medicine 2018, 7, 212-219.

Zheng, Q.; Tong, M.; Ou, B.; Liu, C.; Hu, C.; Yang, Y. Isorhamnetin protects against bleomycin-induced pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial-mesenchymal transition. Int. J. Mol. Med. 2019, 43, 117-126.

Rajasekar, N.; Sivanantham, A.; Kar, A.; Mahapatra, S.K.; Ahirwar, R.; Thimmulappa, R.K.; Paramasivam, S.G.; Subbiah, R. Tannic acid alleviates experimental pulmonary fibrosis in mice by inhibiting inflammatory response and fibrotic process. Inflammopharmacology 2020, 28, 1301-1314.

Pulivendala, G.; Bale, S.; Godugu, C. Honokiol: A polyphenol neolignan ameliorates pulmonary fibrosis by inhibiting TGF-beta/Smad signaling, matrix proteins and IL-6/CD44/STAT3 axis both in vitro and in vivo. Toxicol. Appl. Pharmacol. 2020, 391, 114913.

Qu, M.; Zhou, Z.; Chen, C.; Li, M.; Pei, L.; Chu, F.; Yang, J.; Wang, Y.; Li, L.; Liu, C.; Zhang, L.; Zhang, G.; Yu, Z.; Wang, D. Lycopene protects against trimethyltin-induced neurotoxicity in primary cultured rat hippocampal neurons by inhibiting the mitochondrial apoptotic pathway. Neurochem. Int. 2011, 59, 1095-1103.