Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2005

Open Access 01-12-2005 | Research article

Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity

Authors: Zahid N Rabbani, Mitchell S Anscher, Rodney J Folz, Emerald Archer, Hong Huang, Liguang Chen, Maria L Golson, Thaddeus S Samulski, Mark W Dewhirst, Zeljko Vujaskovic

Published in: BMC Cancer | Issue 1/2005

Login to get access

Abstract

Background

Acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase of injury. Ultimately, complete structural ablation will ensue, if the source of inflammatory / fibrogenic mediators and oxidative stress is not removed or attenuated. Therefore, the purpose of this study is to determine whether overexpression of extracellular superoxide dismutase (EC-SOD) in mice ameliorates acute radiation induced injury by inhibiting activation of TGFβ1 and downregulating the Smad 3 arm of its signal transduction pathway.

Methods

Whole thorax radiation (single dose, 15 Gy) was delivered to EC-SOD overexpressing transgenic (XRT-TG) and wild-type (XRT-WT) animals. Mice were sacrificed at 1 day, 1 week, 3, 6, 10 and 14 weeks. Breathing rates, right lung weights, total/differential leukocyte count, activated TGFβ1 and components of its signal transduction pathway (Smad 3 and p-Smad 2/3) were assessed to determine lung injury.

Results

Irradiated wild-type (XRT-WT) animals exhibited time dependent increase in breathing rates and right lung weights, whereas these parameters were significantly less increased (p < 0.05) at 3, 6, 10 and 14 weeks in irradiated transgenic (XRT-TG) mice. An inflammatory response characterized predominantly by macrophage infiltration was pronounced in XRT-WT mice. This acute inflammation was significantly attenuated (p < 0.05) in XRT-TG animals at 1, 3, 6 and 14 weeks. Expression of activated TGFβ1 and components of its signal transduction pathway were significantly reduced (p < 0.05) at later time-points in XRT-TG vs. XRT-WT.

Conclusion

This study shows that overexpression of EC-SOD confers protection against RT-induced acute lung injury. EC-SOD appears to work, in part, via an attenuation of the macrophage response and also decreases TGFβ1 activation with a subsequent downregulation of the profibrotic TGFβ pathway.
Appendix
Available only for authorised users
Literature
1.
Vujaskovic Z, Marks LB, Anscher MS: The physical parameters and molecular events associated with radiation-induced lung toxicity. Semin Radiat Oncol. 2000, 10 (4): 296-307.CrossRefPubMed
2.
Stone HB, Coleman CN, Anscher MS, McBride WH: Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol. 2003, 4 (9): 529-536. 10.1016/S1470-2045(03)01191-4.CrossRefPubMed
3.
Martin M, Lefaix J, Delanian S: TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target?. Int J Radiat Oncol Biol Phys. 2000, 47 (2): 277-290. 10.1016/S0360-3016(00)00435-1.CrossRefPubMed
4.
Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN: A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995, 33 (1): 99-109. 10.1016/0360-3016(95)00095-G.CrossRefPubMed
5.
Rubin P, Finkelstein J, Shapiro D: Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: interrelationship between the alveolar macrophage and the septal fibroblast. Int J Radiat Oncol Biol Phys. 1992, 24 (1): 93-101.CrossRefPubMed
6.
Hill RP, Rodemann HP, Hendry JH, Roberts SA, Anscher MS: Normal tissue radiobiology: from the laboratory to the clinic. Int J Radiat Oncol Biol Phys. 2001, 49 (2): 353-365. 10.1016/S0360-3016(00)01484-X.CrossRefPubMed
7.
Crystal RG: Oxidants and respiratory tract epithelial injury: pathogenesis and strategies for therapeutic intervention. Am J Med. 1991, 91 (3C): 39S-44S. 10.1016/0002-9343(91)90282-3.CrossRefPubMed
8.
Borok Z, Buhl R, Grimes GJ, Bokser AD, Hubbard RC, Holroyd KJ, Roum JH, Czerski DB, Cantin AM, Crystal RG: Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet. 1991, 338 (8761): 215-216. 10.1016/0140-6736(91)90350-X.CrossRefPubMed
9.
Riley PA: Free radicals in biology: oxidative stress and the effects of ionizing radiation. Int J Radiat Biol. 1994, 65 (1): 27-33.CrossRefPubMed
10.
Marklund SL: Extracellular superoxide dismutase and other superoxide dismutase isoenzymes in tissues from nine mammalian species. Biochem J. 1984, 222 (3): 649-655.CrossRefPubMedPubMedCentral
11.
Folz RJ, Guan J, Seldin MF, Oury TD, Enghild JJ, Crapo JD: Mouse extracellular superoxide dismutase: primary structure, tissue-specific gene expression, chromosomal localization, and lung in situ hybridization. Am J Respir Cell Mol Biol. 1997, 17 (4): 393-403.CrossRefPubMed
12.
Oury TD, Crapo JD, Valnickova Z, Enghild JJ: Human extracellular superoxide dismutase is a tetramer composed of two disulphide-linked dimers: a simplified, high-yield purification of extracellular superoxide dismutase. Biochem J. 1996, 317 ( Pt 1): 51-57.CrossRef
13.
Kang SK, Rabbani ZN, Folz RJ, Golson ML, Huang H, Yu D, Samulski TS, Dewhirst MW, Anscher MS, Vujaskovic Z: Overexpression of extracellular superoxide dismutase protects mice from radiation-induced lung injury. Int J Radiat Oncol Biol Phys. 2003, 57 (4): 1056-1066. 10.1016/S0360-3016(03)01369-5.CrossRefPubMed
14.
Bowler RP, Nicks M, Warnick K, Crapo JD: Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2002, 282 (4): L719-26.CrossRefPubMed
15.
Folz RJ, Abushamaa AM, Suliman HB: Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. J Clin Invest. 1999, 103 (7): 1055-1066.CrossRefPubMedPubMedCentral
16.
Arkovitz MS, Garcia VF, Szabo C, McConnell K, Bove K, Wispe JR: Decreased pulmonary compliance is an early indicator of pulmonary oxygen injury. J Surg Res. 1997, 67 (2): 193-198. 10.1006/jsre.1996.4980.CrossRefPubMed
17.
Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981, 29 (4): 577-580.CrossRefPubMed
18.
Rubin P, Casarett GW: Clinical radiation pathology as applied to curative radiotherapy. Cancer. 1968, 22 (4): 767-778.CrossRefPubMed
19.
Travis EL, Down JD, Holmes SJ, Hobson B: Radiation pneumonitis and fibrosis in mouse lung assayed by respiratory frequency and histology. Radiat Res. 1980, 84 (1): 133-143.CrossRefPubMed
20.
Penney DP, Rubin P: Specific early fine structural changes in the lung irradiation. Int J Radiat Oncol Biol Phys. 1977, 2 (11-12): 1123-1132.CrossRefPubMed
21.
Penney DP, Siemann DW, Rubin P, Shapiro DL, Finkelstein J, Cooper RAJ: Morphologic changes reflecting early and late effects of irradiation of the distal lung of the mouse: a review. Scan Electron Microsc. 1982, 413-425.
22.
Steinberg F, Quabeck K, Rehn B, Kraus R, Mohnke M, Costabel U, Kreuzfelder E, Molls M, Bruch J, Schaefer UW, et al: Lung effects after total body irradiation of mice and bone marrow transplant patients: comparison of experimental and preliminary clinical data. Recent Results Cancer Res. 1993, 130: 133-143.CrossRefPubMed
23.
Ward PA, Hunninghake GW: Lung inflammation and fibrosis. Am J Respir Crit Care Med. 1998, 157 (4 Pt 2): S123-9.CrossRefPubMed
24.
Hagiwara SI, Ishii Y, Kitamura S: Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med. 2000, 162 (1): 225-231.CrossRefPubMed
25.
MacNee W, Rahman I: Oxidants/antioxidants in idiopathic pulmonary fibrosis. Thorax. 1995, 50 Suppl 1: S53-8.CrossRefPubMed
26.
Johnston CJ, Williams JP, Okunieff P, Finkelstein JN: Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor families. Radiat Res. 2002, 157 (3): 256-265.CrossRefPubMed
27.
Suliman HB, Ryan LK, Bishop L, Folz RJ: Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase. Am J Physiol Lung Cell Mol Physiol. 2001, 280 (1): L69-78.PubMed
28.
Akaike T, Noguchi Y, Ijiri S, Setoguchi K, Suga M, Zheng YM, Dietzschold B, Maeda H: Pathogenesis of influenza virus-induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc Natl Acad Sci U S A. 1996, 93 (6): 2448-2453. 10.1073/pnas.93.6.2448.CrossRefPubMedPubMedCentral
29.
Oda T, Akaike T, Hamamoto T, Suzuki F, Hirano T, Maeda H: Oxygen radicals in influenza-induced pathogenesis and treatment with pyran polymer-conjugated SOD. Science. 1989, 244 (4907): 974-976.CrossRefPubMed
30.
Carlsson LM, Jonsson J, Edlund T, Marklund SL: Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci U S A. 1995, 92 (14): 6264-6268.CrossRefPubMedPubMedCentral
31.
Fattman CL, Chang LY, Termin TA, Petersen L, Enghild JJ, Oury TD: Enhanced bleomycin-induced pulmonary damage in mice lacking extracellular superoxide dismutase. Free Radic Biol Med. 2003, 35 (7): 763-771. 10.1016/S0891-5849(03)00402-7.CrossRefPubMed
32.
Vignaud JM, Allam M, Martinet N, Pech M, Plenat F, Martinet Y: Presence of platelet-derived growth factor in normal and fibrotic lung is specifically associated with interstitial macrophages, while both interstitial macrophages and alveolar epithelial cells express the c-sis proto-oncogene. Am J Respir Cell Mol Biol. 1991, 5 (6): 531-538.CrossRefPubMed
33.
Martinet Y, Rom WN, Grotendorst GR, Martin GR, Crystal RG: Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med. 1987, 317 (4): 202-209.CrossRefPubMed
34.
Matsushima K, Taguchi M, Kovacs EJ, Young HA, Oppenheim JJ: Intracellular localization of human monocyte associated interleukin 1 (IL 1) activity and release of biologically active IL 1 from monocytes by trypsin and plasmin. J Immunol. 1986, 136 (8): 2883-2891.PubMed
35.
Beutler B, Cerami A: Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987, 316 (7): 379-385.CrossRefPubMed
36.
Gospodarowicz D, Neufeld G, Schweigerer L: Fibroblast growth factor. Mol Cell Endocrinol. 1986, 46 (3): 187-204. 10.1016/0303-7207(86)90001-8.CrossRefPubMed
37.
Assoian RK, Fleurdelys BE, Stevenson HC, Miller PJ, Madtes DK, Raines EW, Ross R, Sporn MB: Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987, 84 (17): 6020-6024.CrossRefPubMedPubMedCentral
38.
Graham MM, Evans ML, Dahlen DD, Mahler PA, Rasey JS: Pharmacological alteration of the lung vascular response to radiation. Int J Radiat Oncol Biol Phys. 1990, 19 (2): 329-339.CrossRefPubMed
39.
Roberts AB, Russo A, Felici A, Flanders KC: Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta. Ann N Y Acad Sci. 2003, 995: 1-10.CrossRefPubMed
40.
Wang Q, Wang Y, Hyde DM, Gotwals PJ, Koteliansky VE, Ryan ST, Giri SN: Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters. Thorax. 1999, 54 (9): 805-812.CrossRefPubMedPubMedCentral
41.
Rabbani ZN, Anscher MS, Zhang X, Chen L, Samulski TV, Li CY, Vujaskovic Z: Soluble TGFbeta type II receptor gene therapy ameliorates acute radiation-induced pulmonary injury in rats. Int J Radiat Oncol Biol Phys. 2003, 57 (2): 563-572. 10.1016/S0360-3016(03)00639-4.CrossRefPubMed
42.
Nakao A, Fujii M, Matsumura R, Kumano K, Saito Y, Miyazono K, Iwamoto I: Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest. 1999, 104 (1): 5-11.CrossRefPubMedPubMedCentral
43.
Flanders KC, Sullivan CD, Fujii M, Sowers A, Anzano MA, Arabshahi A, Major C, Deng C, Russo A, Mitchell JB, Roberts AB: Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol. 2002, 160 (3): 1057-1068.CrossRefPubMedPubMedCentral
44.
Datto MB, Frederick JP, Pan L, Borton AJ, Zhuang Y, Wang XF: Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol. 1999, 19 (4): 2495-2504.CrossRefPubMedPubMedCentral
45.
Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C: Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. Embo J. 1999, 18 (5): 1280-1291. 10.1093/emboj/18.5.1280.CrossRefPubMedPubMedCentral
46.
Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB: Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999, 1 (5): 260-266. 10.1038/12971.CrossRefPubMed
47.
Flanders KC, Major CD, Arabshahi A, Aburime EE, Okada MH, Fujii M, Blalock TD, Schultz GS, Sowers A, Anzano MA, Mitchell JB, Russo A, Roberts AB: Interference with transforming growth factor-beta/ Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am J Pathol. 2003, 163 (6): 2247-2257.CrossRefPubMedPubMedCentral
Metadata
Title
Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity
Authors
Zahid N Rabbani
Mitchell S Anscher
Rodney J Folz
Emerald Archer
Hong Huang
Liguang Chen
Maria L Golson
Thaddeus S Samulski
Mark W Dewhirst
Zeljko Vujaskovic
Publication date
01-12-2005
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2005
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-5-59

Other articles of this Issue 1/2005

BMC Cancer 1/2005 Go to the issue

Research article

Half versus full vacuum suction drainage after modified radical mastectomy for breast cancer- a prospective randomized clinical trial[ISRCTN24484328]

Research article

Cancer cell adaptation to chemotherapy

Research article

Global gene expression analysis in time series following N-acetyl L-cysteine induced epithelial differentiation of human normal and cancer cells in vitro

Research article

Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy

Research article

Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells

Research article

Expression of transforming growth factor-beta-1 and p27Kip1 in pancreatic adenocarcinomas: relation with cell-cycle-associated proteins and clinicopathologic characteristics
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits