Modulation of Cytokine and Nitric Oxide by Mesenchymal Stem Cell Transfer in Lung Injury/fibrosis

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2010 Feb 9

PMID 20137099

Citations 72

Authors

Shin-Hwa Lee

An-Soo Jang

Young-Eun Kim

Ji-Yeon Cha

Tae-Hoon Kim

Seok Jung

Seong-Kyu Park

You-Kyoung Lee

Jong-Ho Won

Yong-Hoon Kim

Choon-Sik Park

Affiliations

Soon will be listed here.

Abstract

Background: No effective treatment for acute lung injury and fibrosis currently exists. Aim of this study was to investigate the time-dependent effect of bone marrow-derived mesenchymal stem cells (BMDMSCs) on bleomycin (BLM)-induced acute lung injury and fibrosis and nitric oxide metabolites and inflammatory cytokine production.

Methods: BMDMSCs were transferred 4 days after BLM inhalation. Wet/dry ratio, bronchoalveolar lavage cell profiles, histologic changes and deposition of collagen were analyzed.

Results: Nitrite, nitrate and cytokines were measured weekly through day 28. At day 7, the wet/dry ratio, neutrophilic inflammation, and amount of collagen were elevated in BLM-treated rats compared to sham rats (p = 0.05-0.002). Levels nitrite, nitrate, IL-1beta, IL-6, TNF-alpha, TGF-beta and VEGF were also higher at day 7 (p < 0.05). Degree of lymphocyte and macrophage infiltration increased steadily over time. BMDMSC transfer significantly reduced the BLM-induced increase in wet/dry ratio, degree of neutrophilic infiltration, collagen deposition, and levels of the cytokines, nitrite, and nitrate to those in sham-treated rats (p < 0.05). Fluorescence in situ hybridization localized the engrafted cells to areas of lung injury.

Conclusion: Systemic transfer of BMDMSCs effectively reduced the BLM-induced lung injury and fibrosis through the down-regulation of nitric oxide metabolites, and proinflammatory and angiogenic cytokines.

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References

Janes K, Gaudet S, Albeck J, Nielsen U, Lauffenburger D, Sorger P . The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell. 2006; 124(6):1225-39. DOI: 10.1016/j.cell.2006.01.041. View

Rojas M, Xu J, Woods C, Mora A, Spears W, Roman J . Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005; 33(2):145-52. PMC: 2715309. DOI: 10.1165/rcmb.2004-0330OC. View

Schrier D, Kunkel R, Phan S . The role of strain variation in murine bleomycin-induced pulmonary fibrosis. Am Rev Respir Dis. 1983; 127(1):63-6. DOI: 10.1164/arrd.1983.127.1.63. View

Olman M, White K, Ware L, Simmons W, Benveniste E, Zhu S . Pulmonary edema fluid from patients with early lung injury stimulates fibroblast proliferation through IL-1 beta-induced IL-6 expression. J Immunol. 2004; 172(4):2668-77. DOI: 10.4049/jimmunol.172.4.2668. View

Henke C, Marineili W, Jessurun J, Fox J, Harms D, Peterson M . Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury. Am J Pathol. 1993; 143(4):1189-99. PMC: 1887071. View

Harrison Jr J, Lazo J . High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis. J Pharmacol Exp Ther. 1987; 243(3):1185-94. View

Kotton D, Ma B, Cardoso W, Sanderson E, Summer R, Williams M . Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development. 2001; 128(24):5181-8. DOI: 10.1242/dev.128.24.5181. View

Yen C, Yang S, Lin C, Chen C . Stem cells in the lung parenchyma and prospects for lung injury therapy. Eur J Clin Invest. 2006; 36(5):310-9. DOI: 10.1111/j.1365-2362.2006.01638.x. View

da Silva Meirelles L, Nardi N . Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization. Br J Haematol. 2003; 123(4):702-11. DOI: 10.1046/j.1365-2141.2003.04669.x. View

10.

Jang A, Lee J, Choi I, Park K, Lee J, Park S . Expression of nitric oxide synthase, aquaporin 1 and aquaporin 5 in rat after bleomycin inhalation. Intensive Care Med. 2004; 30(3):489-95. DOI: 10.1007/s00134-003-2129-9. View

11.

Fehrenbach H . Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res. 2001; 2(1):33-46. PMC: 59567. DOI: 10.1186/rr36. View

12.

Kolb M, Margetts P, Anthony D, Pitossi F, Gauldie J . Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest. 2001; 107(12):1529-36. PMC: 200196. DOI: 10.1172/JCI12568. View

13.

Kaner R, Ladetto J, Singh R, Fukuda N, Matthay M, Crystal R . Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema. Am J Respir Cell Mol Biol. 2000; 22(6):657-64. DOI: 10.1165/ajrcmb.22.6.3779. View

14.

Gaston B, Drazen J, Loscalzo J, Stamler J . The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med. 1994; 149(2 Pt 1):538-51. DOI: 10.1164/ajrccm.149.2.7508323. View

15.

Krause D, Theise N, Collector M, Henegariu O, Hwang S, Gardner R . Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001; 105(3):369-77. DOI: 10.1016/s0092-8674(01)00328-2. View

16.

Jiang Y, Jahagirdar B, Reinhardt R, Schwartz R, Keene C, Ortiz-Gonzalez X . Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002; 418(6893):41-9. DOI: 10.1038/nature00870. View

17.

Prockop D . Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997; 276(5309):71-4. DOI: 10.1126/science.276.5309.71. View

18.

Kuwano K, Nakashima N, Inoshima I, Hagimoto N, Fujita M, Yoshimi M . Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias. Eur Respir J. 2003; 21(2):232-40. DOI: 10.1183/09031936.03.00063203. View

19.

MacCallum N, Evans T . Epidemiology of acute lung injury. Curr Opin Crit Care. 2005; 11(1):43-9. DOI: 10.1097/00075198-200502000-00007. View

20.

Karmpaliotis D, Kosmidou I, Ingenito E, Hong K, Malhotra A, Sunday M . Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2002; 283(3):L585-95. DOI: 10.1152/ajplung.00048.2002. View