Geranylgeranylacetone alleviates radiation-induced lung injury by inhibiting epithelial-to-mesenchymal transition signaling

Kim,Joong‑Sun; Son,Yeonghoon; Jung,Myung‑Gu; Jeong,Ye  Ji; Kim,Sung‑Ho; Lee,Su‑Jae; Lee,Yoon‑Jin; Lee,Hae‑June

doi:10.3892/mmr.2016.5121

Geranylgeranylacetone alleviates radiation-induced lung injury by inhibiting epithelial-to-mesenchymal transition signaling

Authors:
- Joong‑Sun Kim
- Yeonghoon Son
- Myung‑Gu Jung
- Ye Ji Jeong
- Sung‑Ho Kim
- Su‑Jae Lee
- Yoon‑Jin Lee
- Hae‑June Lee
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Affiliations: Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619‑953, Republic of Korea, Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139‑706, Republic of Korea, Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University, Gwangju 500‑757, Republic of Korea, Laboratory of Molecular Biochemistry, Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 133‑791, Republic of Korea
Published online on: April 13, 2016 https://doi.org/10.3892/mmr.2016.5121
Pages: 4666-4670

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Abstract

Radiation-induced lung injury (RILI) involves pneumonitis and fibrosis, and results in pulmonary dysfunction. Moreover, RILI can be a fatal complication of thoracic radiotherapy. The present study investigated the protective effect of geranylgeranlyacetone (GGA), an inducer of heat shock protein (HSP)70, on RILI using a C57BL/6 mouse model of RILI developing 6 months subsequent to exposure to 12.5 Gy thoracic radiation. GGA was administered 5 times orally prior and subsequent to radiation exposure, and the results were assessed by histological analysis and western blotting. The results show that late RILI was alleviated by GGA treatment, possibly through the suppression of epithelial‑to‑mesenchymal transition (EMT) marker expression. Based on histological examination, orally administered GGA during the acute phase of radiation injury not only significantly inhibited pro‑surfactant protein C (pro‑SPC) and vimentin expression, but also preserved E‑cadherin expression 6 months after irradiation‑induced injury of the lungs. GGA induced HSP70 and inhibited EMT marker expression in L132 human lung epithelial cells following IR. These data suggest that the prevention of EMT signaling is a key cytoprotective effect in the context of RILI. Thus, HSP70‑inducing drugs, such as GGA, could be beneficial for protection against RILI.

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1	McDonald S, Rubin P, Phillips TL and Marks LB: Injury to the lung from cancer therapy: Clinical syndromes, measurable endpoints and potential scoring systems. Int J Radiat Oncol Biol Phys. 31:1187–1203. 1995. View Article : Google Scholar : PubMed/NCBI
2	Robnett TJ, Machtay M, Vines EF, McKenna MG, Algazy KM and McKenna WG: Factors predicting severe radiation pneu-monitis in patients receiving definitive chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys. 48:89–94. 2000. View Article : Google Scholar : PubMed/NCBI
3	Hughes-Davies L, Tarbell NJ, Coleman CN, Silver B, Shulman LN, Linggood R, Canellos GP and Mauch PM: Stage IA-IIB Hodgkin's disease: Management and outcome of extensive thoracic involvement. Int J Radiat Oncol Biol Phys. 39:361–369. 1997. View Article : Google Scholar : PubMed/NCBI
4	Cappuccini F, Eldh T, Bruder D, Gereke M, Jastrow H, Schulze-Osthoff K, Fischer U, Köhler D, Stuschke M and Jendrossek V: New insights into the molecular pathology of radiation-induced pneumopathy. Radiother Oncol. 101:86–92. 2011. View Article : Google Scholar : PubMed/NCBI
5	Wynn TA: Integrating mechanisms of pulmonary fibrosis. J Exp Med. 208:1339–1350. 2011. View Article : Google Scholar : PubMed/NCBI
6	Balli D, Ustiyan V, Zhang Y, Wang IC, Masino AJ, Ren X, Whitsett JA, Kalinichenko VV and Kalin TV: Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition. EMBO J. 32:231–244. 2013. View Article : Google Scholar : PubMed/NCBI
7	Pozharskaya V, Torres-González E, Rojas M, Gal A, Amin M, Dollard S, Roman J, Stecenko AA and Mora AL: Twist: A regulator of epithelial-mesenchymal transition in lung fibrosis. PLoS One. 4:e7559–e7510. 2009. View Article : Google Scholar : PubMed/NCBI
8	Hodge S, Holmes M, Banerjee B, Musk M, Kicic A, Waterer G, Reynolds PN, Hodge G and Chambers DC: Posttransplant bronchiolitis obliterans syndrome is associated with bronchial epithelial to mesenchymal transition. Am J Transplant. 9:727–733. 2009. View Article : Google Scholar : PubMed/NCBI
9	Almeida C, Nagarajan D, Tian J, Leal SW, Wheeler K, Munley M, Blackstock W and Zhao W: The role of alveolar epithelium in radiation-induced lung injury. PLoS One. 8:e536282013. View Article : Google Scholar : PubMed/NCBI
10	Mao H, Li Z, Zhou Y, Li Z, Zhuang S, An X, Zhang B, Chen W, Nie J, Wang Z, et al: HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol. 295:F202–F214. 2008. View Article : Google Scholar : PubMed/NCBI
11	Tanaka K, Tanaka Y, Namba T, Azuma A and Mizushima T: Heat shock protein 70 protects against bleomycin-induced pulmonary fibrosis in mice. Biochem Pharmacol. 80:920–931. 2010. View Article : Google Scholar : PubMed/NCBI
12	Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T and Yoshioka H: Association between heat stress protein 70 induction and decreased pulmonary fibrosis in an animal model of acute lung injury. Lung. 185:287–293. 2007. View Article : Google Scholar : PubMed/NCBI
13	Niu P, Liu L, Gong Z, Tan H, Wang F, Yuan J, Feng Y, Wei Q, Tanguay RM and Wu T: Overexpressed heat shock protein 70 protects cells against DNA damage caused by ultraviolet C in a dose-dependent manner. Cell Stress Chaperones. 11:162–169. 2006. View Article : Google Scholar : PubMed/NCBI
14	Kawana K, Miyamoto Y, Tanonaka K, Han-no Y, Yoshida H, Takahashi M and Takeo S: Cytoprotective mechanism of heat shock protein 70 against hypoxia/reoxygenation injury. J Mol Cell Cardiol. 32:2229–2237. 2000. View Article : Google Scholar : PubMed/NCBI
15	Hirakawa T, Rokutan K, Nikawa T and Kishi K: Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology. 111:345–357. 1996. View Article : Google Scholar : PubMed/NCBI
16	Niwa Y, Nakamura M, Miyahara R, Ohmiya N, Watanabe O, Ando T, Kawashima H, Itoh A, Hirooka Y and Goto H: Geranylgeranylacetone protects against diclofenac-induced gastric and small intestinal mucosal injuries in healthy subjects: A prospective randomized placebo-controlled double-blind cross-over study. Digestion. 80:260–266. 2009. View Article : Google Scholar : PubMed/NCBI
17	Liu J, Bao J, Hao J, Peng Y and Hong F: HSP70 inhibits high glucose-induced Smad3 activation and attenuates epithelial-to-mesenchymal transition of peritoneal mesothelial cells. Mol Med Rep. 10:1089–1095. 2014.PubMed/NCBI
18	Zhang Y, Zhang X, Shan P, Hunt CR, Pandita TK and Lee PJ: A protective Hsp70-TLR4 pathway in lethal oxidant lung injury. J Immunol. 191:1393–1403. 2013. View Article : Google Scholar : PubMed/NCBI
19	Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D and Chapman HA: Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA. 103:13180–13185. 2006. View Article : Google Scholar : PubMed/NCBI
20	Adamson IY, Young L and Bowden DH: Relationship of alveolar epithelial injury and repair to the induction of pulmonary fibrosis. Am J Pathol. 130:377–383. 1988.PubMed/NCBI
21	Takeichi M: Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 251:1451–1455. 1991. View Article : Google Scholar : PubMed/NCBI