Abstract
Idiopathic pulmonary fibrosis is characterised by abnormal reepithelialisation and remodelling consequent to persistent stimuli or injury. The involvement of oxidative stress in alveolar injury, inflammation and fibrosis development has been suggested. Increased concentrations of lipid peroxidation products, oxidised proteins and an altered antioxidant enzyme status with the depletion of glutathione, the most abundant low-molecular-weight antioxidant, have often been reported in epithelial lining fluid of IPF patients. This review describes the sources of free radical generation, ROS-induced signalling pathways and mechanisms of oxidative stress damages in the pathogenesis of idiopathic pulmonary fibrosis.
Similar content being viewed by others
Abbreviations
- IPF:
-
Idiopathic pulmonary fibrosis
- HRCT:
-
High-resolution computed tomography of the chest
- ILD:
-
Interstitial lung diseases
References
Cottin, V., F. Capron, P. Grenier, and J.F. Cordier. 2004. Diffuse idiopathic interstitial pneumonias, international multidisciplinary consensus classification by the American Thoracic Society and the European Respiratory Society, principal clinico-pathological entities, and diagnosis. Revue des Maladies Respiratoires 21 (2 Pt 1): 299–318.
Raghu, G., H.R. Collard, J.J. Egan, F.J. Martinez, J. Behr, K.K. Brown, T.V. Colby, J.F. Cordier, K.R. Flaherty, J.A. Lasky, D.A. Lynch, J.H. Ryu, J.J. Swigris, A.U. Wells, J. Ancochea, D. Bouros, C. Carvalho, U. Costabel, M. Ebina, D.M. Hansell, T. Johkoh, D.S. Kim, King te Jr, Y. Kondoh, J. Myers, N.L. Müller, A.G. Nicholson, L. Richeldi, M. Selman, R.F. Dudden, B.S. Griss, S.L. Protzko, H.J. Schünemann, and ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. 2011. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. American Journal of Respiratory and Critical Care Medicine 183: 788–824.
Nalysnyk, L., J. Cid-Ruzafa, P. Rotella, and D. Esser. 2012. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. European Respiratory Review 21: 355–361.
Fois, A.G., P. Paliogiannis, S. Sotgia, A.A. Mangoni, E. Zinellu, P. Pirina, C. Carru, and A. Zinellu. 2018. Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review. Respiratory Research 19 (1): 51.
Johannson, K.A., J.R. Balmes, and H.R. Collard. 2015. Air pollution exposure: a novel environmental risk factor for interstitial lung disease? Chest 147 (4): 1161–1167.
Raghu, G., B. Rochwerg, Y. Zhang, C.A. Garcia, A. Azuma, J. Behr, J.L. Brozek, H.R. Collard, W. Cunningham, S. Homma, T. Johkoh, F.J. Martinez, J. Myers, S.L. Protzko, L. Richeldi, D. Rind, M. Selman, A. Theodore, A.U. Wells, H. Hoogsteden, H.J. Schünemann, and American Thoracic Society., European Respiratory society., Japanese Respiratory Society., Latin American Thoracic Association. 2015. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 192: e3–e19.
Hilberg, O., U. Simonsen, R. du Bois, and E. Bendstrup. 2012. Pirfenidone: significant treatment effects in idiopathic pulmonary fibrosis. The Clinical Respiratory Journal 6 (3): 131–143.
Wollin, L., I. Maillet, V. Quesniaux, A. Holweg, and B. Ryffel. 2014. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. The Journal of Pharmacology and Experimental Therapeutics 349 (2): 209–220.
Magi, B., E. Bargagli, L. Bini, and P. Rottoli. 2006. Proteome analysis of bronchoalveolar lavage in lung diseases. Proteomics. 6: 6354–6369.
Rottoli, P., B. Magi, M.G. Perari, S. Liberatori, N. Nikiforakis, E. Bargagli, R. Cianti, L. Bini, and V. Pallini. 2005. Cytokine profile and proteome analysis in BAL of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics. 5: 1423–1430.
Ahmad, S., M.Y. Khan, Z. Rafi, H. Khan, Z. Siddiqui, S. Rehman, U. Shahab, M.S. Khan, M. Saeed, S. Alouffi, and M.S. Khan. 2018. Oxidation, glycation and glycoxidation - the vicious cycle and lung cancer. Seminars in Cancer Biology 49: 29–36.
Gawda, A., G. Majka, B. Nowak, et al. 2017. Air pollution, oxidative stress, and exacerbation of autoimmune diseases. Central-European Journal of Immunology 42 (3): 305–312.
Gonzalez-Gonzalez, F.J., N.S. Chandel, M. Jain, and G.R.S. Budinger. 2017. Reactive oxygen species as signaling molecules in the development of lung fibrosis. Translational Research 190: 61–68.
Ferrari, R.S., and C.F. Andrade. 2015. Oxidative stress and lung ischemia-reperfusion injury. Oxidative Medicine and Cellular Longevity 2015: 590987.
Chanda, D., E. Otoupalova, S.R. Smith, T. Volckaert, S.P. De Langhe, and V.J. Thannickal. 2019. Developmental pathways in the pathogenesis of lung fibrosis. Molecular Aspects of Medicine 65: 56–69.
Landi, C., E. Bargagli, A. Carleo, L. Bianchi, A. Gagliardi, A. Prasse, M.G. Perari, R.M. Refini, L. Bini, and P. Rottoli. 2014. A system biology study of BALF from patients affected by idiopathic pulmonary fibrosis (IPF) and healthy controls. Proteomics. Clinical Applications 8 (11–12): 932–950.
Liu, X., and Z. Chen. 2017. The pathophysiological role of mitochondrial oxidative stress in lung diseases. Journal of Translational Medicine 15 (1): 207.
Liguori, I., G. Russo, F. Curcio, G. Bulli, L. Aran, D. Della-Morte, G. Gargiulo, G. Testa, F. Cacciatore, D. Bonaduce, and P. Abete. 2018. Oxidative stress, aging, and diseases. Clinical Interventions in Aging 13: 757–772.
Rottoli, P., B. Magi, R. Cianti, E. Bargagli, C. Vagaggini, N. Nikiforakis, V. Pallini, and L. Bini. 2005. Carbonylated proteins in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 5 (10): 2612–2618.
Bargagli, E., F. Penza, C. Vagaggini, B. Magi, M.G. Perari, and P. Rottoli. 2007. Analysis of carbonylated proteins in bronchoalveolar lavage of patients with diffuse lung diseases. Lung. 185 (3): 139–144.
Malli, F., F. Bardaka, I. Tsilioni, E. Karetsi, K.I. Gourgoulianis, and Z. Daniil. 2013. 8-isoprostane levels in serum and bronchoalveolar lavage in idiopathic pulmonary fibrosis and sarcoidosis. Food and Chemical Toxicology 61: 160–163.
Bargagli, E., F. Monaci, N. Bianchi, C. Bucci, and P. Rottoli. 2008. Analysis of trace elements in bronchoalveolar lavage of patients with diffuse lung diseases. Biological Trace Element Research 124 (3): 225–235.
Bargagli, E., F. Lavorini, M. Pistolesi, E. Rosi, A. Prasse, E. Rota, and L. Voltolini. 2017. Trace metals in fluids lining the respiratory system of patients with idiopathic pulmonary fibrosis and diffuse lung diseases. Journal of Trace Elements in Medicine and Biology 42: 39–44.
Sangiuolo, F., E. Puxeddu, G. Pezzuto, F. Cavalli, G. Longo, A. Comandini, D. di Pierro, M. Pallante, G. Sergiacomi, G. Simonetti, M. Zompatori, A. Orlandi, A. Magrini, M. Amicosante, F. Mariani, M. Losi, D. Fraboni, A. Bisetti, and C. Saltini. 2015. HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis. The European Respiratory Journal 45 (2): 483–490.
Lee, J., I. Arisi, E. Puxeddu, L.K. Mramba, M. Amicosante, C.M. Swaisgood, M. Pallante, M.L. Brantly, C.M. Sköld, and C. Saltini. 2018. Bronchoalveolar lavage (BAL) cells in idiopathic pulmonary fibrosis express a complex pro-inflammatory, pro-repair, angiogenic activation pattern, likely associated with macrophage iron accumulation. PLoS One 13 (4): e0194803.
O'Dwyer, D.N., and B.B. Moore. 2019. Iron-ing out the roles of macrophages in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine.
Ye, Q., Y. Dalavanga, N. Poulakis, S.U. Sixt, J. Guzman, and U. Costabel. 2008. Decreased expression of haem oxygenase-1 by alveolar macrophages in idiopathic pulmonary fibrosis. The European Respiratory Journal 31 (5): 1030–1036.
Iwata, Y., M. Okamoto, T. Hoshino, Y. Kitasato, Y. Sakazaki, M. Tajiri, K. Matsunaga, K. Azuma, T. Kawayama, T. Kinoshita, H. Imaoka, K. Fujimoto, S. Kato, H. Yano, and H. Aizawa. 2010. Elevated levels of thioredoxin 1 in the lungs and sera of idiopathic pulmonary fibrosis, non-specific interstitial pneumonia and cryptogenic organizing pneumonia. Internal Medicine 49 (22): 2393–2400.
Gorowiec, M.R., L.A. Borthwick, S.M. Parker, J.A. Kirby, G.C. Saretzki, and A.J. Fisher. 2012. Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-ß1-dependent mechanism. Free Radical Biology & Medicine 52 (6): 1024–1032.
Schamberger, A.C., H.B. Schiller, I.E. Fernandez, et al. 2016. Glutathione peroxidase 3 localizes to the epithelial lining fluid and the extracellular matrix in interstitial lung disease. Scientific Reports 6: 29952.
Hecker, L., R. Vittal, T. Jones, R. Jagirdar, T.R. Luckhardt, J.C. Horowitz, S. Pennathur, F.J. Martinez, and V.J. Thannickal. 2009. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nature Medicine 15: 1077–1081.
Watson, W.H., J.D. Ritzenthaler, and J. Roman. 2016. Lung extracellular matrix and redox regulation. Redox Biology 8: 305–315.
Hecker, L., N.J. Logsdon, D. Kurundkar, A. Kurundkar, K. Bernard, T. Hock, E. Meldrum, Y.Y. Sanders, and V.J. Thannickal. 2014. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Science Translational Medicine 6: 231ra47.
Zhou, Y., X. Huang, L. Hecker, D. Kurundkar, A. Kurundkar, H. Liu, T.H. Jin, L. Desai, K. Bernard, and V.J. Thannickal. 2013. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. The Journal of Clinical Investigation 123 (3): 1096–1108.
Pardo, A., S. Cabrera, M. Maldonado, and M. Selman. 2016. Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Respiratory Research 17: 23. https://doi.org/10.1186/s12931-016-0343-6 Review.
Estany, S., V. Vicens-Zygmunt, R. Llatjós, A. Montes, R. Penín, I. Escobar, A. Xaubet, S. Santos, F. Manresa, J. Dorca, and M. Molina-Molina. 2014. Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1. BMC Pulmonary Medicine 14: 120.
Kliment, C.R., and T.D. Oury. 2010. Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Free Radical Biology & Medicine 49 (5): 707–717.
Chen, X., C. Shi, H. Cao, L. Chen, J. Hou, Z. Xiang, K. Hu, and X. Han. 2018. The hedgehog and Wnt/ß-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell Death & Disease 9 (6): 639.
Zeidler, P., A. Hubbs, L. Battelli, and V. Castranova. 2004. Role of inducible nitric oxide synthase-derived nitric oxide in silica-induced pulmonary inflammation and fibrosis. Journal of Toxicology and Environmental Health. Part A 67 (13): 1001–1026.
Ricciardolo, F.L., P.J. Sterk, B. Gaston, and G. Folkerts. 2004. Nitric oxide in health and disease of the respiratory system. Physiological Reviews 84 (3): 731–765.
Romanska, H.M., J.M. Polak, R.A. Coleman, R.S. James, D.W. Harmer, J.C. Allen, and A.E. Bishop. 2002. iNOS gene upregulation is associated with the early proliferative response of human lung fibroblasts to cytokine stimulation. The Journal of Pathology 197 (3): 372–379.
Saleh, D., P.J. Barnes, and A. Giaid. 1997. Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 155 (5): 1763–1769.
Hsu, Y.-C., L.-F. Wang, and Y.W. Chien. 2007. Nitric oxide in the pathogenesis of diffuse pulmonary fibrosis. Free Radical Biology & Medicine 42 (5): 599–607.
Pullamsetti, S.S., R. Savai, R. Dumitrascu, B.K. Dahal, J. Wilhelm, M. Konigshoff, D. Zakrzewicz, and Ghofrani. 2011. The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. Science Translational Medicine 3: 87ra53.
Cameli, P., E. Bargagli, R.M. Refini, M.G. Pieroni, D. Bennett, and P. Rottoli. 2014. Exhaled nitric oxide in interstitial lung diseases. Respiratory Physiology & Neurobiology 197: 46–52.
Cameli, P., E. Bargagli, and P. Rottoli. 2016. Exhaled nitric oxide is not increased in pulmonary sarcoidosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases 33 (1): 39–40.
Cameli, P., E. Bargagli, L. Bergantini, R.M. Refini, M. Pieroni, P. Sestini, and P. Rottoli. 2019. Evaluation of multiple-flows exhaled nitric oxide in idiopathic and non-idiopathic interstitial lung disease. Journal of Breath Research.
Walters, D.M., H.Y. Cho, and S.R. Kleeberger. 2008. Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxidants & Redox Signaling 10 (2): 321–332.
Liu, Y., F. Lu, L. Kang, Z. Wang, and Y. Wang. 2017. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC Pulmonary Medicine 17 (1): 63.
Mazur, W., P. Lindholm, K. Vuorinen, et al. 2010. Cell-specific elevation of NRF2 and sulfiredoxin-1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. APMIS 118 (9): 703–712.
Carleo, A., E. Bargagli, C. Landi, D. Bennett, L. Bianchi, A. Gagliardi, C. Carnemolla, M.G. Perari, G. Cillis, A. Armini, L. Bini, and P. Rottoli. 2016. Comparative proteomic analysis of bronchoalveolar lavage of familial and sporadic cases of idiopathic pulmonary fibrosis. Journal of Breath Research 10 (2): 026007.
Chilosi, M., A. Carloni, A. Rossi, and V. Poletti. 2013. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Translational Research 162 (3): 156–173.
Villegas, L., T. Stidham, and E. Nozik-Grayck. 2014. Oxidative stress and therapeutic development in lung diseases. Journal of Pulmonary & Respiratory Medicine 4 (4).
Idiopathic Pulmonary Fibrosis Clinical Research Network, F.J. Martinez, J.A. de Andrade, K.J. Anstrom, T.E. King Jr., and G. Raghu. 2014. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. The New England Journal of Medicine 370 (22): 2093–2101. https://doi.org/10.1056/NEJMoa1401739.
Oldham, J.M., S.F. Ma, F.J. Martinez, et al. 2015. TOLLIP, MUC5B, and the response to N-Acetylcysteine among individuals with idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 192 (12): 1475–1482.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The study was developed at Siena University.
Rights and permissions
About this article
Cite this article
Cameli, P., Carleo, A., Bergantini, L. et al. Oxidant/Antioxidant Disequilibrium in Idiopathic Pulmonary Fibrosis Pathogenesis. Inflammation 43, 1–7 (2020). https://doi.org/10.1007/s10753-019-01059-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-019-01059-1