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Radiation Oncology
Published in: Radiation Oncology 1/2015

Open Access 01-12-2015 | Research

Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice

Authors: Alexandra Paun, Amit Kunwar, Christina K Haston

Published in: Radiation Oncology | Issue 1/2015

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Abstract

Background

The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later.

Methods

Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10–23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed.

Results

Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R = −0.80, p = 0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R = 0.81, p = 0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains.

Conclusion

Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains.
Appendix
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Literature
1.
Osterreicher J, Pejchal J, Skopek J, Mokry J, Vilasova Z, Psutka J, et al. Role of type II pneumocytes in pathogenesis of radiation pneumonitis: dose response of radiation-induced lung changes in the transient high vascular permeability period. Exp Toxicol Pathol. 2004;56:181–7.CrossRefPubMed
2.
Van der Meeren A, Vandamme M, Squiban C, Gaugler MH, Mouthon MA. Inflammatory reaction and changes in expression of coagulation proteins on lung endothelial cells after total-body irradiation in mice. Radiat Res. 2003;160:637–46.CrossRefPubMed
3.
Roberts CM, Foulcher E, Zaunders JJ, Bryant DH, Freund J, Cairns D, et al. Radiation pneumonitis: a possible lymphocyte-mediated hypersensitivity reaction. Ann Intern Med. 1993;118:696–700.CrossRefPubMed
4.
Takigawa N, Segawa Y, Saeki T, Kataoka M, Ida M, Kishino D, et al. Bronchiolitis obliterans organizing pneumonia syndrome in breast-conserving therapy for early breast cancer: radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2000;48:751–5.CrossRefPubMed
5.
Rube CE, Uthe D, Wilfert F, Ludwig D, Yang K, Konig J, et al. The bronchiolar epithelium as a prominent source of pro-inflammatory cytokines after lung irradiation. Int J Radiat Oncol Biol Phys. 2005;61:1482–92.CrossRefPubMed
6.
Kuwano K, Hagimoto N, Nakanishi Y. The role of apoptosis in pulmonary fibrosis. Histol Histopathol. 2004;19:867–81.PubMed
7.
Abe S, Boyer C, Liu X, Wen FQ, Kobayashi T, Fang Q, et al. Cells derived from the circulation contribute to the repair of lung injury. Am J Respir Crit Care Med. 2004;170:1158–63.CrossRefPubMed
8.
Epperly MW, Guo H, Gretton JE, Greenberger JS. Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29:213–24.CrossRefPubMed
9.
Russell NS, Grummels A, Hart AA, Smolders IJ, Borger J, Bartelink H, et al. Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. Int J Radiat Biol. 1998;73:661–70.CrossRefPubMed
10.
Peacock J, Ashton A, Bliss J, Bush C, Eady J, Jackson C, et al. Cellular radiosensitivity and complication risk after curative radiotherapy. Radiother Oncol. 2000;55:173–8.CrossRefPubMed
11.
Brock WA, Tucker SL, Geara FB, Turesson I, Wike J, Nyman J, et al. Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. Int J Radiat Oncol Biol Phys. 1995;32:1371–9.CrossRefPubMed
12.
Burnet NG, Nyman J, Turesson I, Wurm R, Yarnold JR, Peacock JH. Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity. Lancet. 1992;339:1570–1.CrossRefPubMed
13.
Herskind C, Bamberg M, Rodemann HP. The role of cytokines in the development of normal-tissue reactions after radiotherapy. Strahlenther Onkol. 1998;174 Suppl 3:12–5.PubMed
14.
Chen Y, Williams J, Ding I, Hernady E, Liu W, Smudzin T, et al. Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol. 2002;12:26–33.CrossRefPubMed
15.
Chen Y, Hyrien O, Williams J, Okunieff P, Smudzin T, Rubin P. Interleukin (IL)-1A and IL-6: applications to the predictive diagnostic testing of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2005;62:260–6.CrossRefPubMed
16.
Arpin D, Perol D, Blay JY, Falchero L, Claude L, Vuillermoz-Blas S, et al. Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis. J Clin Oncol. 2005;23:8748–56.CrossRefPubMed
17.
Stenmark MH, Cai XW, Shedden K, Hayman JA, Yuan S, Ritter T, et al. Combining physical and biologic parameters to predict radiation-induced lung toxicity in patients with non-small-cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 2012;84:e217–22.CrossRefPubMedCentralPubMed
18.
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;33:99–109.CrossRefPubMed
19.
McBride WH. Cytokine cascades in late normal tissue radiation responses. Int J Radiat Oncol Biol Phys. 1995;33:233–4.CrossRefPubMed
20.
Sharplin J, Franko AJ. A quantitative histological study of strain-dependent differences in the effects of irradiation on mouse lung during the intermediate and late phases. Radiat Res. 1989;119:15–31.CrossRefPubMed
21.
Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;294:L152–60.CrossRefPubMed
22.
Paun A, Haston CK. Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice. Radiother Oncol. 2012;105:350–7.CrossRefPubMed
23.
Thomas DM, Fox J, Haston CK. Imatinib therapy reduces radiation-induced pulmonary mast cell influx and delays lung disease in the mouse. Int J Radiat Biol. 2010;86:436–44.CrossRefPubMed
24.
Johnston CJ, Williams JP, Elder A, Hernady E, Finkelstein JN. Inflammatory cell recruitment following thoracic irradiation. Exp Lung Res. 2004;30:369–82.CrossRefPubMed
25.
Haston CK, Begin M, Dorion G, Cory SM. Distinct loci influence radiation-induced alveolitis from fibrosing alveolitis in the mouse. Cancer Res. 2007;67:10796–803.CrossRefPubMed
26.
Wirsdörfer F, Cappuccini F, Niazman M, de Leve S, Westendorf AM, Lüdemann L, et al. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells. Radiat Oncol. 2014;9:98.CrossRefPubMedCentralPubMed
27.
Toma CL, Serbescu A, Alexe M, Cervis L, Ionita D, Bogdan MA. The bronchoalveolar lavage pattern in radiation pneumonitis secondary to radiotherapy for breast cancer. Maedica (Buchar). 2010;5:250–7.
28.
Han G, Zhang H, Xie CH, Zhou YF. Th2-like immune response in radiation-induced lung fibrosis. Oncol Rep. 2011;26:383–8.PubMed
29.
Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol. 2013;8:477–512.CrossRefPubMedCentralPubMed
30.
Chiang CS, Liu WC, Jung SM, Chen FH, Wu CR, McBride WH, et al. Compartmental responses after thoracic irradiation of mice: strain differences. Int J Radiat Oncol Biol Phys. 2005;62:862–71.CrossRefPubMed
31.
Paun A, Lemay AM, Haston CK. Gene expression profiling distinguishes radiation-induced fibrosing alveolitis from alveolitis in mice. Radiat Res. 2010;173:512–21.CrossRefPubMed
32.
Hackstein H, Wachtendorf A, Kranz S, Lohmeyer J, Bein G, Baal N. Heterogeneity of respiratory dendritic cell subsets and lymphocyte populations in inbred mouse strains. Respir Res. 2012;13:94.CrossRefPubMedCentralPubMed
33.
O'Brien TJ, Letuve S, Haston CK. Radiation-induced strain differences in mouse alveolar inflammatory cell apoptosis. Can J Physiol Pharmacol. 2005;83:117–22.CrossRefPubMed
34.
Lemay AM, Haston CK. Radiation-induced lung response of AcB/BcA recombinant congenic mice. Radiat Res. 2008;170:299–306.CrossRefPubMed
35.
Fox J, Gordon JR, Haston CK. Combined CXCR1/CXCR2 antagonism decreases radiation-induced alveolitis in the mouse. Radiat Res. 2011;175:657–64.CrossRefPubMed
36.
Paun A, Fox J, Balloy V, Chignard M, Qureshi ST, Haston CK. Combined Tlr2 and Tlr4 deficiency increases radiation-induced pulmonary fibrosis in mice. Int J Radiat Oncol Biol Phys. 2010;77:1198–205.CrossRefPubMed
37.
Rube CE, Wilfert F, Palm J, Konig J, Burdak-Rothkamm S, Liu L, et al. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. Strahlenther Onkol. 2004;180:442–8.PubMed
38.
Barthelemy-Brichant N, Bosquee L, Cataldo D, Corhay JL, Gustin M, Seidel L, et al. Increased IL-6 and TGF-beta1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy. Int J Radiat Oncol Biol Phys. 2004;58:758–67.CrossRefPubMed
39.
Gasse P, Riteau N, Vacher R, Michel ML, Fautrel A, di Padova F, et al. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis. PLoS One. 2011;6:e23185.CrossRefPubMedCentralPubMed
40.
Westermann W, Schobl R, Rieber EP, Frank KH. Th2 cells as effectors in postirradiation pulmonary damage preceding fibrosis in the rat. Int J Radiat Biol. 1999;75:629–38.CrossRefPubMed
41.
Nakagome K, Dohi M, Okunishi K, Tanaka R, Miyazaki J, Yamamoto K. In vivo IL-10 gene delivery attenuates bleomycin induced pulmonary fibrosis by inhibiting the production and activation of TGF-beta in the lung. Thorax. 2006;61:886–94.CrossRefPubMedCentralPubMed
42.
Antonadou D, Coliarakis N, Synodinou M, Athanassiou H, Kouveli A, Verigos C, et al. Randomized phase III trial of radiation treatment +/− amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys. 2001;51:915–22.CrossRefPubMed
43.
Reckzeh B, Merte H, Pfluger KH, Pfab R, Wolf M, Havemann K. Severe lymphocytopenia and interstitial pneumonia in patients treated with paclitaxel and simultaneous radiotherapy for non-small-cell lung cancer. J Clin Oncol. 1996;14:1071–6.PubMed
44.
Graves PR, Siddiqui F, Anscher MS, Movsas B. Radiation pulmonary toxicity: from mechanisms to management. Semin Radiat Oncol. 2010;20:201–7.CrossRefPubMed
45.
Ao X, Zhao L, Davis MA, Lubman DM, Lawrence TS, Kong FM. Radiation produces differential changes in cytokine profiles in radiation lung fibrosis sensitive and resistant mice. J Hematol Oncol. 2009;2:6.CrossRefPubMedCentralPubMed
46.
Hong JH, Chiang CS, Tsao CY, Lin PY, McBride WH, Wu CJ. Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation. Int J Radiat Biol. 1999;75:1421–7.CrossRefPubMed
47.
Johnston CJ, Hernady E, Reed C, Thurston SW, Finkelstein JN, Williams JP. Early alterations in cytokine expression in adult compared to developing lung in mice after radiation exposure. Radiat Res. 2010;173:522–35.CrossRefPubMedCentralPubMed
48.
McBride WH, Vegesna V. The role of T-cells in radiation pneumonitis after bone marrow transplantation. Int J Radiat Biol. 2000;76:517–21.CrossRefPubMed
49.
McBride WH, Vegesna V. Role of the thymus in radiation-induced lung damage after bone marrow transplantation. Radiat Res. 1997;147:501–5.CrossRefPubMed
50.
Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res. 1995;21:791–808.CrossRefPubMed
51.
Kimura T, Ishii Y, Morishima Y, Shibuya A, Shibuya K, Taniguchi M, et al. Treatment with alpha-galactosylceramide attenuates the development of bleomycin-induced pulmonary fibrosis. J Immunol. 2004;172:5782–9.CrossRefPubMed
52.
Pochetuhen K, Luzina IG, Lockatell V, Choi J, Todd NW, Atamas SP. Complex regulation of pulmonary inflammation and fibrosis by CCL18. Am J Pathol. 2007;171:428–37.CrossRefPubMedCentralPubMed
53.
Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, et al. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med. 2010;207:535–52.CrossRefPubMedCentralPubMed
54.
Lo Re S, Lison D, Huaux F. CD4+ T lymphocytes in lung fibrosis: diverse subsets, diverse functions. J Leukoc Biol. 2013;93:499–510.CrossRefPubMed
55.
Hong JH, Jung SM, Tsao TC, Wu CJ, Lee CY, Chen FH, et al. Bronchoalveolar lavage and interstitial cells have different roles in radiation-induced lung injury. Int J Radiat Biol. 2003;79:159–67.CrossRefPubMed
56.
Liu W, Ding I, Chen K, Olschowka J, Xu J, Hu D, et al. Interleukin 1beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis. Radiat Res. 2006;165:181–91.CrossRefPubMed
57.
Sabat R, Grutz G, Warszawska K, Kirsch S, Witte E, Wolk K, et al. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010;21:331–44.CrossRefPubMed
58.
McBride WH, Chiang CS, Olson JL, Wang CC, Hong JH, Pajonk F, et al. A sense of danger from radiation. Radiat Res. 2004;162:1–19.CrossRefPubMed
Metadata
Title
Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice
Authors
Alexandra Paun
Amit Kunwar
Christina K Haston
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2015
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/s13014-015-0359-y

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