Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats

Huang,Kun; Kang,Xiaowen; Wang,Xinyan; Wu,Shijie; Xiao,Jinling; Li,Zhaoguo; Wu,Xiaomei; Zhang,Wei

doi:10.3892/mmr.2014.2981

Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats

Authors:
- Kun Huang
- Xiaowen Kang
- Xinyan Wang
- Shijie Wu
- Jinling Xiao
- Zhaoguo Li
- Xiaomei Wu
- Wei Zhang
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Affiliations: Department of Respiratory Medicine, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Respiratory Medicine, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163316, P.R. China, Department of Respiratory Medicine, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: November 19, 2014 https://doi.org/10.3892/mmr.2014.2981
Pages: 1685-1692
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Pulmonary fibrosis is an irreversible chronic progressive fibroproliferative lung disease, which usually has a poor prognosis. Previous studies have confirmed that the transplantation of bone marrow mesenchymal stem cells (MSCs) significantly reduces lung damage in a number of animal models. However, the underlying mechanism involved in this process remains to be elucidated. In the present study, a bleomycin (BLM)‑induced female Wister rat model of fibrosis was established. At 0 or 7 days following BLM administration, rats were injected into the tail vein with 5‑bromo‑2‑deoxyuridine‑labeled MSCs extracted from male Wistar rats. The lung tissue of the rats injected with MSCs expressed the sex‑determining region Y gene. The level surfactant protein C (SP‑C), a marker for type II alveolar epithelial cells (AEC II), was higher in the group injected with MSCs at day 0 than that in the group injected at day 7. Furthermore, SP‑C mRNA, but not aquaporin 5 mRNA, a marker for type I alveolar epithelial cells, was expressed in fresh bone marrow aspirates and the fifth generation of cultured MSCs. In addition, superoxide dismutase activity and total antioxidative capability, specific indicators of oxidative stress, were significantly increased in the lung tissue of the MSC‑transplanted rats (P<0.05). In conclusion, to alleviate pulmonary fibrosis, exogenous MSCs may be transplanted into damaged lung tissue where they differentiate into AEC II and exert their effect, at least in part, through blocking oxidative stress.

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1	Fernandez IE and Eickelberg O: New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet. 380:680–688. 2012. View Article : Google Scholar : PubMed/NCBI
2	Crestani B, Marchand-Adam S, Fabre A, Dehoux M and Soler P: Mechanisms in pulmonary fibrosis. Rev Prat. 57:2222–2226. 2007.(In French).
3	Nuovo GJ, Hagood JS, Magro CM, et al: The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis. Mod Pathol. 25:416–433. 2012. View Article : Google Scholar :
4	Starosta V, Ratjen F, Rietschel E, Paul K and Griese M: Anti-inflammatory cytokines in cystic fibrosis lung disease. Eur Respir J. 28:581–587. 2006. View Article : Google Scholar : PubMed/NCBI
5	Simonian PL, Roark CL, Born WK, O’Brien RL and Fontenot AP: Gammadelta T cells and Th17 cytokines in hypersensitivity pneumonitis and lung fibrosis. Transl Res. 154:222–227. 2009. View Article : Google Scholar : PubMed/NCBI
6	Tan HL, Regamey N, Brown S, et al: The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med. 184:252–258. 2011. View Article : Google Scholar : PubMed/NCBI
7	Okada M, Suzuki K, Matsumoto M, et al: Effects of angiotensin on the expression of fibrosis-associated cytokines, growth factors, and matrix proteins in human lung fibroblasts. J Clin Pharm Ther. 34:288–299. 2009. View Article : Google Scholar : PubMed/NCBI
8	Ruan W and Ying K: Abnormal expression of IGF-binding proteins, an initiating event in idiopathic pulmonary fibrosis? Pathol Res Pract. 206:537–543. 2010. View Article : Google Scholar : PubMed/NCBI
9	Datta A, Scotton CJ and Chambers RC: Novel therapeutic approaches for pulmonary fibrosis. Br J Pharmacol. 163:141–172. 2011. View Article : Google Scholar : PubMed/NCBI
10	Maher TM: Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment. Clin Chest Med. 33:69–83. 2012. View Article : Google Scholar : PubMed/NCBI
11	Sisson TH, Mendez M, Choi K, et al: Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 181:254–263. 2010. View Article : Google Scholar :
12	Kliment CR and Oury TD: Oxidative stress, extracellular matrix targets, and idiopathic pulmonary fibrosis. Free Radic Biol Med. 49:707–717. 2010. View Article : Google Scholar : PubMed/NCBI
13	El-Khouly D, El-Bakly WM, Awad AS, El-Mesallamy HO and El-Demerdash E: Thymoquinone blocks lung injury and fibrosis by attenuating bleomycin-induced oxidative stress and activation of nuclear factor Kappa-B in rats. Toxicology. 302:106–113. 2012. View Article : Google Scholar : PubMed/NCBI
14	Cheresh P, Kim SJ, Tulasiram S and Kamp DW: Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta. 1832.1028–1040. 2012.
15	Lu TH, Chen CH, Lee MJ, et al: Methylmercury chloride induces alveolar type II epithelial cell damage through an oxidative stress-related mitochondrial cell death pathway. Toxicol Lett. 194:70–78. 2010. View Article : Google Scholar : PubMed/NCBI
16	Shi C: Recent progress toward understanding the physiological function of bone marrow mesenchymal stem cells. Immunology. 136:133–138. 2012. View Article : Google Scholar : PubMed/NCBI
17	Charbord P: Bone marrow mesenchymal stem cells: historical overview and concepts. Hum Gene Ther. 21:1045–1056. 2010. View Article : Google Scholar : PubMed/NCBI
18	Daba MH, El-Tahir KE, Al-Arifi MN and Gubara OA: Drug-induced pulmonary fibrosis. Saudi Med J. 25:700–706. 2004.PubMed/NCBI
19	Kan I, Melamed E and Offen D: Integral therapeutic potential of bone marrow mesenchymal stem cells. Curr Drug Targets. 6:31–41. 2005. View Article : Google Scholar : PubMed/NCBI
20	Jiang Y, Jahagirdar BN, Reinhardt RL, et al: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 418:41–49. 2002. View Article : Google Scholar : PubMed/NCBI
21	Kotton DN, Ma BY, Cardoso WV, et al: Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development. 128:5181–5188. 2001.PubMed/NCBI
22	Ortiz LA, Gambelli F, McBride C, et al: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA. 100:8407–8411. 2003. View Article : Google Scholar : PubMed/NCBI
23	Mora AL and Rojas M: Aging and lung injury repair: a role for bone marrow derived mesenchymal stem cells. J Cell Biochem. 105:641–647. 2008. View Article : Google Scholar : PubMed/NCBI
24	Li HP, Li X, He GJ, Yi XH and Kaplan AP: The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin-induced pulmonary fibrosis in rats. Respirology. 9:25–32. 2004. View Article : Google Scholar : PubMed/NCBI
25	Padilla-Nash HM, Barenboim-Stapleton L, Difilippantonio MJ and Ried T: Spectral karyotyping analysis of human and mouse chromosomes. Nat Protoc. 1:3129–3142. 2006. View Article : Google Scholar
26	Zhao F, Zhang YF, Liu YG, et al: Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats. Transplant Proc. 40:1700–1705. 2008. View Article : Google Scholar : PubMed/NCBI
27	Feng SW, Yao XL, Li Z, et al: In vitro bromodeoxyuridine labeling of rat bone marrow-derived mesenchymal stem cells. Di Yi Jun Yi Da Xue Xue Bao. 25:184–186. 2005.(In Chinese). PubMed/NCBI
28	Dominici M, Le Blanc K, Mueller I, et al: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI
29	Li X, Zhang Y and Qi G: Evaluation of isolation methods and culture conditions for rat bone marrow mesenchymal stem cells. Cytotechnology. 65:323–334. 2013. View Article : Google Scholar :
30	Szapiel SV, Elson NA, Fulmer JD, Hunninghake GW and Crystal RG: Bleomycin induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir Dis. 120:893–899. 1979.PubMed/NCBI
31	Tanaka K, Ishihara T, Azuma A, et al: Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 298:L348–L360. 2010. View Article : Google Scholar
32	Narahara M, Yamada A, Hamada-Kanazawa M, Kawai Y and Miyake M: cDNA cloning of the Sry-related gene Sox6 from rat with tissue-specific expression. Biol Pharm Bull. 25:705–709. 2002. View Article : Google Scholar : PubMed/NCBI
33	Liu J, Wang X, Wang F, Teng L and Cao J: Attenuation effects of heparin-superoxide dismutase conjugate on bleomycin-induced lung fibrosis in vivo and radiation-induced inflammatory cytokine expression in vitro. Biomed Pharmacother. 63:484–491. 2009. View Article : Google Scholar
34	Wei X, Liu H, Sun X, et al: Hydroxysafflor yellow A protects rat brains against ischemia-reperfusion injury by antioxidant action. Neurosci Lett. 386:58–62. 2005. View Article : Google Scholar : PubMed/NCBI
35	Qi HP, Wei SQ, Gao XC, et al: Ursodeoxycholic acid prevents selenite-induced oxidative stress and alleviates cataract formation: In vitro and in vivo studies. Mol Vis. 18:151–160. 2012.PubMed/NCBI
36	Bowden DH: Unraveling pulmonary fibrosis: the bleomycin model. Lab Invest. 50:487–488. 1984.PubMed/NCBI
37	Wang D, Haviland DL, Burns AR, Zsigmond E and Wetsel RA: A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc Natl Acad Sci USA. 104:4449–4454. 2007. View Article : Google Scholar : PubMed/NCBI
38	Wang D, Morales JE, Calame DG, Alcorn JL and Wetsel RA: Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice. Mol Ther. 18:625–634. 2010. View Article : Google Scholar : PubMed/NCBI
39	Kapanci Y, Weibel ER, Kaplan HP and Robinson FR: Pathogenesis and reversibility of the pulmonary lesions of oxygen toxicity in monkeys. II. Ultrastructural and morphometric studies. Lab Invest. 20:101–118. 1969.PubMed/NCBI
40	Castranova V, Rabovsky J, Tucker JH and Miles PR: The alveolar type II epithelial cell: a multifunctional pneumocyte. Toxicol Appl Pharmacol. 93:472–483. 1988. View Article : Google Scholar : PubMed/NCBI
41	Fehrenbach H: Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res. 2:33–46. 2001. View Article : Google Scholar : PubMed/NCBI
42	Emura M, Ochiai A, Singh G, et al: In vitro reconstitution of human respiratory epithelium. In Vitro Cell Dev Biol Anim. 33:602–605. 1997. View Article : Google Scholar : PubMed/NCBI
43	Jiang Y, Jahagirdar BN, Reinhardt RL, et al: Pluripoteney of mesenehymal stem cells derived from adult marrow. Nature. 418:41–49. 2002. View Article : Google Scholar : PubMed/NCBI
44	Ablin RJ: The need for personalized therapy and companion diagnostics in prostate cancer. Biomark Med. 5:281–283. 2011. View Article : Google Scholar : PubMed/NCBI
45	Caspary WJ, Lanzo DA and Niziak C: Effect of deoxyribonucleic acid on the production of reduced oxygen by bleomycin and iron. Biochemistry. 21:334–338. 1982. View Article : Google Scholar : PubMed/NCBI