Review Article

Efficacy of Alveolar Type II Epithelial Cell Transplantation for Pulmonary Fibrosis: A Meta-Analysis


Background: Cell transplantation is a promising therapeutic strategy for pulmonary fibrosis. In order to clarify the alveolar type II epithelial cell potential utility in the treatment of lung disease, we conducted a meta-analysis, to evaluate alveolar type II epithelial cells in animal models of lung injury and pulmonary fibrosis.

Methods: This review followed the recommendations from the PRISMA statements, Comprehensive retrieval method was used to search Embase, PubMed, Cochrane, Chinese Knowledge Infrastructure, VIP and Wanfang databases. A total of 7 studies and 286 model rats were included. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. All analyses were conducted using Review Manager V.5.3 software. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed or random-effects models.

Results: The analysis of three outcome indexes showed that the heterogeneity of the oxygen saturation group was high (I2=85%), the lung weight group (I2=64%) was close to moderate heterogeneity, and the lung hydroxyproline content group (I2=0) was not heterogeneous.

Conclusion: Meta-analysis showed that transplantation of alveolar type II epithelial cells has beneficial effects, and no obvious adverse reactions. Alveolar type II epithelial cell transplantation can significantly reduce the intervention group and lung hydroxyproline content weight, improve the blood oxygen saturation, lung histopathology showed significant improvement in pulmonary fibrosis.


1. Raghu G, Remy-Jardin, M, Myers, JL, et al (2018). Diagnosis of idiopathic pulmo-nary fibrosis. An official ats/ers/jrs/alat clinical practice guideline. Am J Respir Crit Care Med, 198(5): e44-e68.
2. Olson AL, Gifford, AH, Inase, N, et al (2018). The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. Eur Respir Rev, 27(150) 180077.
3. Herrera J, Henke, CA, Bitterman, PB (2018). Extracellular matrix as a driver of pro-gressive fibrosis. J Clin Invest, 128(1): 45-53.
4. Lynch DA, Sverzellati, N, Travis, WD, et al (2018). Diagnostic criteria for idiopathic pulmonary fibrosis: A fleischner society white paper. Lancet Respir Med, 6(2): 138-153.
5. Raghu G, Rochwerg, B, Zhang, Y, et al (2015). An official ats/ers/jrs/alat clinical practice guideline: Treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med, 192(2): e3-19.
6. Duckworth A, Gibbons, MA, Allen, RJ, et al (2021). Telomere length and risk of idio-pathic pulmonary fibrosis and chronic obstructive pulmonary disease: A mende-lian randomisation study. Lancet Respir Med, 9(3): 285-294.
7. Wells AU, Flaherty, KR, Brown, KK, et al (2020). Nintedanib in patients with pro-gressive fibrosing interstitial lung diseas-es-subgroup analyses by interstitial lung disease diagnosis in the inbuild trial: A randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med, 8(5): 453-460.
8. Crestani B, Huggins, JT, Kaye, M, et al (2019). Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: Results from the open-label extension study, inpulsis-on. Lancet Respir Med, 7(1): 60-68.
9. Noble PW, Albera, C, Bradford, WZ, et al (2011). Pirfenidone in patients with idio-pathic pulmonary fibrosis (capacity): Two randomised trials. Lancet, 377(9779): 1760-1769.
10. Kolilekas L, Papiris, S, Bouros, D (2019). Existing and emerging treatments for id-iopathic pulmonary fibrosis. Expert Rev Respir Med, 13(3): 229-239.
11. Serrano-Mollar A, Gay-Jordi, G, Guillamat-Prats, R, et al (2016). Safety and tolerabil-ity of alveolar type ii cell transplantation in idiopathic pulmonary fibrosis. Chest, 150(3): 533-543.
12. Mason RJ, Williams, MC (1977). Type ii al-veolar cell. Defender of the alveolus. Am Rev Respir Dis, 115(6 Pt 2): 81-91.
13. Fehrenbach H (2001). Alveolar epithelial type ii cell: Defender of the alveolus revisited. Respir Res, 2(1): 33-46.
14. Wu A, Song, H (2020). Regulation of alveo-lar type 2 stem/progenitor cells in lung injury and regeneration. Acta Biochim Bio-phys Sin (Shanghai), 52(7): 716-722.
15. Lottes RG, Newton, DA, Spyropoulos, DD, et al (2014). Alveolar type ii cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adapta-tion. Am J Physiol Lung Cell Mol Physiol, 306(10): L947-955.
16. Serrano-Mollar A, Nacher, M, Gay-Jordi, G, et al (2007). Intratracheal transplantation of alveolar type ii cells reverses bleomy-cin-induced lung fibrosis. Am J Respir Crit Care Med, 176(12): 1261-1268.
17. Spitalieri P, Quitadamo, MC, Orlandi, A, et al (2012). Rescue of murine silica-induced lung injury and fibrosis by human em-bryonic stem cells. Eur Respir J, 39(2): 446-457.
18. Li Y, Gu, C, Xu, W, et al (2014). Therapeutic effects of amniotic fluid-derived mesen-chymal stromal cells on lung injury in rats with emphysema. Respir Res, 15(1): 120.
19. Moher D, Liberati, A, Tetzlaff, J, et al (2009). Preferred reporting items for systematic reviews and meta-analyses: The prisma statement. BMJ, 339: b2535.
20. Song S, Fu, Z, Guan, R, et al (2022). Intracel-lular hydroxyproline imprinting following resolution of bleomycin-induced pulmo-nary fibrosis. Eur Respir J, 59(5).
21. Wahlström E, Ollerstam, A, Sundius, L, et al (2013). Use of lung weight as biomarker for assessment of lung toxicity in rat in-halation studies. Toxicol Pathol, 41(6): 902-912.
22. Hook JL, Arcasoy, SM, Zemmel, D, et al (2012). Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis. Eur Respir J, 39(2): 359-365.
23. Hooijmans CR, Rovers, MM, de Vries, RB, et al (2014). Syrcle's risk of bias tool for animal studies. BMC Med Res Methodol, 14: 43.
24. DerSimonian R, Kacker, R (2007). Random-effects model for meta-analysis of clinical trials: An update. Contemp Clin Trials, 28(2): 105-114.
25. DerSimonian R, Laird, N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7(3): 177-188.
26. Lau J, Ioannidis, JP, Schmid, CH (1997). Quantitative synthesis in systematic re-views. Ann Intern Med, 127(9): 820-826.
27. Guillamat-Prats R, Gay-Jordi, G, Xaubet, A, et al (2014). Alveolar type ii cell transplan-tation restores pulmonary surfactant pro-tein levels in lung fibrosis. J Heart Lung Transplant, 33(7): 758-765.
28. Alvarez-Palomo B, Sanchez-Lopez, LI, Moodley, Y, et al (2020). Induced plu-ripotent stem cell-derived lung alveolar epithelial type ii cells reduce damage in bleomycin-induced lung fibrosis. Stem Cell Res Ther, 11(1): 213.
29. Wang D, Morales, JE, Calame, DG, et al (2010). Transplantation of human em-bryonic stem cell-derived alveolar epithe-lial type ii cells abrogates acute lung injury in mice. Mol Ther, 18(3): 625-634.
30. Guillamat-Prats R, Puig, F, Camprubí-Rimblas, M, et al (2018). Intratracheal in-stillation of alveolar type ii cells enhances recovery from acute lung injury in rats. J Heart Lung Transplant, 37(6): 782-791.
31. Spitalieri P, Quitadamo, MC, Orlandi, A, et al (2013). Human embryonic stem cells recover in vivo acute lung inflammation bleomycin-induced. Sarcoidosis Vasc Diffuse Lung Dis, 30(3): 177-185.
32. Anonymus (2014). Advancing regenerative medicine. Nat Med, 20(8): 795.
33. Zhang E, Yang, Y, Zhang, J, et al (2019). Efficacy of bone marrow mesenchymal stem cell transplantation in animal mod-els of pulmonary fibrosis after exposure to bleomycin: A meta-analysis. Exp Ther Med, 17(3): 2247-2255.
IssueVol 52 No 1 (2023) QRcode
SectionReview Article(s)
Alveolar type II epithelial cells Stem cells Regenerative medicine Treatment Pulmonary fibrosis

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How to Cite
Zhang W, Wang Y, Du Y, Li Z, Mu Y, Sun J, Liu Z, Guo Y, Shao H, Guan Y, Cui G, Du Z. Efficacy of Alveolar Type II Epithelial Cell Transplantation for Pulmonary Fibrosis: A Meta-Analysis. Iran J Public Health. 2023;52(1):1-9.