Iranian Journal of Allergy, Asthma and Immunology 2017. 16(3):205-218.

Effects of Intraperitoneal Injection of Allogeneic Bone Marrow-derived Mesenchymal Stem Cells on Bronchiolitis Obliterans in Mice Model
Sakine Işık, Nevin Uzuner, Meral Karaman, Özkan Karaman, Müge Kıray, İlknur Kozanoğlu, Hüsnü Alper Bağrıyanık, Zeynep Arıkan-Ayyıldız, Melis Kartal Yandım, Yusuf Baran

Abstract


Bone marrow-derived mesenchymal stem cells (BMSCs) can ameliorate a variety of lung diseases such as asthma, lung fibrosis, and acute lung injury by its anti-inflammatory and immunmodulatory effects. In this study, we developed a mouse model of bronchiolitis obliterans (BO) and evaluated the effects of the intraperitoneal administration of BMSCs on lung histopathology and cytokine levels. 25 BALB/c mice were divided into four groups; control group (Group I), BO developed and 1x10BMSCs-injected group (Group II), non-BO, 1x106 BMSCs-injected group (Group III), and BO developed and saline-injected group (Group IV). Histological and immunohistochemical findings of the lung tissue and the migration of BMSCs to the lung were evaluated using light and confocal microscopy techniques. Confocal microscopy evaluations showed that there was no noteworthy amount of BMSCs in the lung tissue of group III while significant amount of BMSCs was detected in group II. Wall thicknesses of terminal bronchiole and periterminal bronchiolar collagen deposition were significantly lower in group II compared to the group IV (p<0.05). Furthermore, according to the immunohistochemical staining results, CD3, CD4, CD8, CD20, CD68 and neutrophil elastase positive immune cells of group II were stained more positive than group IV cells (p<0.05). IFN-γ IL-2 and TNF-α levels in bronchoalveolar lavage fluid (BALF) were significantly lower in group II compared to group IV (p<0.05). The findings of this study indicate that intraperitoneally administered BMSCs have potent effects on histopatological changes of the lung tissue and cytokine levels in the murine model of BO.


Keywords


Bronchiolitis obliterans; Intraperitoneal administration; Mesenchymal stem cells; Murine model

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References

1) Ryu JH, Myers JL, Swensen SJ.  Bronchiolar disorders. Am J Respir Crit Care Med 2003; 168 (11):1277-92.

2) Chan PWK, Muridan R, Debruyne JA. Bronchiolitis obliterans in children: clinical profile and diagnosis. Respirology 2000; 5(4): 369-75.

3) Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and hematopietic stme cell transplantation. Am J Respir Crit Care Med 2004;170 (1): 22-48.

4) Yalçın E, Doğru D, Haliloğlu M, Özçelik U, Kiper N, Göçmen A. Postinfectious bronchiolitis obliterans in children: clinical and radiological profile and prognostic factors. Respiration 2003; 70 (4): 371-75.

5) Sarahrudi KCarretta AWisser WSenbaklavaci OPloner MNeuhauser P, et al. The value of switching from cyclosporine to tacrolimus in the treatment of refractory acute rejection and obliterative bronchiolitis after lung transplantation. Transplant Int 2002; 15 (1): 24-28.

6) Ding IB, Baumgartner RA, Schwaiblamir M, Behr J. Admistration of anti-interleukine 2Rα monoclonal antibody in bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2003;75 (10) :1767-69.

7) Dosanh A, Ikonen T, Wan B, Morris RE. Pirfenidone: a novel anti-fibrotic agent and progressive chronic allograft rejection. Pulm Pharmacol Ther 2001;15 (5): 433-37.

8) Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2003;168 (1):121-25.

9) Hardy KA, Schidlow DV, Zacri N. Obliterative bronchiolitis in children. Chest 1988; 93 (3): 460-66.

10) Delorme B, Charbord P. Culture and characterization of human bone marrow mesenchymal stem cells. Methods Mol Med 2007;140:67-81.

11) Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284 (5411):143-47.

12) Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006; 98 (5) :1076-84.

13) Loebinger MR, Aguilar S, Janes SM. Therapeutic potential of stem cells in lung disease: progress and pitfalls. Clin Sci (Lond) 2008; 114 (2): 99-108.

14) Firinci F ,  Karaman M, Baran Y, Bagriyanik A, Ayyildiz ZA, Kiray M, et al.Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma. Int Immunopharmacol 2011;  11(8):1120-26.

15) Ortiz LAGambelli FMcBride CGaupp DBaddoo MKaminski N,  et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.Proc Natl Acad Sci U S A 2003;100(14):8407-11.

16) Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T, et al.Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis 2011;1(6): 63-71.

17) Matthay MAThompson BTRead EJMcKenna DH JrLiu KDCalfee CS, , et al.  Therapeutic potential of mesenchymal stem cells for severe acute lung injury.Chest 2010;138(4): 965-72.

18) Garippo AL, Parra ER, Teodoro WR, Veloza AP, Yoshinari NH, Capelozzi VL. Immune cell infiltration and broncovascular remodeling after nitric acid nasal instillation in a mouse bronchiolitis obliterans model. Lung 2006; 184(4):229-38.

19) Sunay O, Can G, Cakir Z, et al (2013)  Autologous Rabbit Adipose Tissue Derived Mesenchymal Stem Cells For The Treatment Of Bone Injuries With Distraction Osteogenesis. Cytotherapy 15(6): 690-702.

20) Baran Y, Ural AU, Avcu F, Sarper M, Elçi P, Pekel A. Optimisation of Transfection of Green Flourescent Protein in Pursuing Mesenchymal Stem Cells, In Vivo. Turkish Journal of Hematology 2008;25(4): 172-75.

21) Aris RM, Walsh S, Chalermskulrat W, Hathwar V, Neuringer IP. Growth factor upregulation during obliterative bronchiolitis in the mouse model. Am J Respir Crit Care Med 2002;166 (3): 417-22.

22) Hertz MI, , Henke CANakhleh REHarmon KRMarinelli WAFox JM,  et al. Obliterative bronchliolitis after lung transplantation: a fibroobliterative disorder associated with platelet-derived growth factor. Proc Natl Acad Sci USA 1992;89 (21) :10385-89.

23) Laohaburanakit P, Chan A, Allen RP. Bronchiolitis obliterans. Clin Rev Allergy Immunol 2003; 25 (3):259-74.

24) Krause DS, Theise ND, Collector MI, Henegariu OHwang SGardner R,  et al. Multiorgan,multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105 (3): 369–77.

25) Kotton DN, Ma BY, Cardoso WV, Sanderson EASummer RSWilliams MC, et al. Bone marrow derived cells as progenitors of lung alveolar epithelium. Development 2001;128 (24):5181–88.

26) Theise ND, Henegariu O, Grove J, Jagirdar J, Kao PN, Crawford JM, et al. Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. Exp Hematol 2002; 30 (11): 1333–38.

27) Ishizawa K, Kubo H, Yamada M, Kobayashi S, Suzuki T, Mizuno S, et al. Hepatocyte growth factor induces angiogenesis in injured lungs through mobilizing endothelial progenitor cells. Biochem Biophys Res Commun 2004; 324 (1):276–80.

28) Mei SH, Haitsma J, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010; 182 (8): 1047–57.

29) Krasnodembskaya A, Song Y, Fang X,  Gupta NSerikov VLee JW,  et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 2010; 28 (12): 2229–38.

30) Guan XJ, Song L, Han FF, Cui ZL, Chen X, Guo XJ, et al. Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem 2013;114(2): 323-35.

31) Lee SH, Jang AS, Kim YE, Cha JY, Kim TH, Jung S, et al. Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis.Respir Res 2010; 8:11-16.

32) Ortiz LA, Dutreil M, Fattman C, Pandey ACTorres GGo K,  et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 2007;104 (26):11002–07.

33) Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S et al. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol 2009; 175(1):303-13.

34)  Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T,  et al.  Unicentric study of cell therapy in chronic obstructive pulmonary disease/ pulmonary emphysema. Int J Chron Obstruct Pulmon Dis 2011; 6: 63–71.

35) Chang YSAhn SYYoo HS,   Sung SI, Choi SJ, Oh WI,.et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr 2014;164(5): 966-72.

36) Zhao MM, Cui JZ, Cui Y, Li RTian YXSong SX, et al.Therapeutic effect of exogenous bone marrowderived mesenchymal stem cell transplantation on silicosis via paracrine mechanisms in rats. Mol Med Rep 2013;8 (3):741-46.

37)  Zhao Y, Xu A, Xu Q, Zhao W, Li D, Fang X, et al. Bone marrow mesenchymal stem cell transplantation for treatment of emphysemic rats.Int J Clin Exp Med 2014;7 (4):968-72.

38) Xie J, Hu D, Niu L, Qu S, Wang S, Liu S. Mesenchymal stem cells attenuate vascular remodeling in monocrotaline-induced pulmonary hypertension rats. J Huazhong Univ Sci Technolog Med Sci 2012;32 (6):810-17.

39) Araujo IM, Abreu SC, Maron-Gutierrez T, Cruz FFujisaki LCarreira H Jr,  et al. Bone marrow-derived mononuclear cell therapy in experimental pulmonary and extrapulmonary acute lung injury. Crit Care Med 2010;38 (8):1733–41.

40) Rojas M., Xu J., Woods C. R., Mora A. L., Spears W.,Roman J. et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am. J. Respir. Cell Mol. Biol 2005; 33(2):145–52.

41) Tian ZFDu JFu XMWang BHong XYFeng ZC. Influence of human bone marrow-derived mesenchymal stem cells on the lung of newborn rats damaged by hyperoxia. Zhonghua Er Ke Za Zhi 2008;46(1):4-8.

42) Abreu SC, Antunes MA, Maron- Gutierrez T, Maron-Gutierrez T, Cruz FF, Carmo LG, et al. Effects of bone marrow-derived mononuclear cells on airway and lung parenchyma remodeling in a murine model of chronic allergic inflammation. Respir Physiol Neurobiol 2010; 175 (1): 153–63.

43)  Mistchenko AS, Diez RA, Mariani AL, Robaldo JMaffey AFBayley-Bustamante G, et al. Cytokines in adenoviraldisease in children: association of interleukine-6, interleukine-8 and tumor necrosis factor alpha levels with clinical outcome. J Pediatr 1994; 124 (5):714-20.

44) Boehler ABai XHLiu MCassivi SChamberlain DSlutsky AS, et al. Upregulation of T-helper 1 cytokines and chemokine expression in post-transplant airway obliteration. Am J Respir Crit Care Med 1999; 159(6):1910-17.

45) Zhao YGillen JRHarris DAKron ILMurphy MPLau CL. Treatment with placenta-derived mesenchymal stem cells mitigates development of bronchiolitis obliterans in a murine model. J Thorac Cardiovasc Surg 2014;147(5):1668-77


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