Use of human amniotic epithelial cells in mouse models of bleomycin-induced lung fibrosis: A systematic review and meta-analysis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) urgently requires effective treatment. Bleomycin-induced lung injury models are characterized by initial inflammation and secondary fibrosis, consistent with the pathological features of IPF. Human amniotic epithelial cells (hAECs) exhibit good differentiation potential and paracrine activity and are thus ideal for cell-based clinical therapies. The therapeutic effects of hAECs on lung fibrosis are attributed to many factors. We performed a systematic review of preclinical studies investigating the treatment of pulmonary fibrosis with hAECs to provide suggestions for their clinical use.

Methods: PubMed and EMBASE were searched for original studies describing hAEC therapy in animal bleomycin-induced pulmonary fibrosis models. After quality assessments, the number and species of experimental animals, bleomycin dose, hAEC source and dosage, time and route of administration of transplanted cells in animals, and time animals were euthanized in nine controlled preclinical studies were summarized. Ashcroft scores, lung collagen contents, inflammatory cells and cytokines were quantitatively and/or qualitatively analyzed in this review. Publication bias was also assessed.

Results: Each of the nine preclinical studies have unique characteristics regarding hAEC use. Ashcroft scores and lung collagen contents were decreased following hAEC transplantation in bleomycin-injured mice. Histopathology was also improved in most studies following treatment with hAECs. hAECs modulated macrophages, neutrophils, T cells, dendritic cells and the mRNA or protein levels of cytokines associated with inflammatory reactions (tumor necrosis factor-α, transforming growth factor-β, interferon-γ and interleukin) in lung tissues of bleomycin-injured mice.

Conclusions: hAECs alleviate and reverse the progression of bleomycin-induced lung fibrosis in mice and may represent a new clinical treatment for IPF. hAECs exert anti-inflammatory and anti-fibrotic effects by modulating macrophage, neutrophil, T cell, dendritic cell and related cytokine levels in mice with bleomycin-induced lung fibrosis. Cell generation and the route, source and timing of hAEC transplantation all determine the therapeutic effectiveness of hAECs.

Fig 1. Included and excluded studies.

Fig 2

Forest Plots of Ashcroft Scores (A) and Lung Collagen Contents (B). CI: confidence interval; IV: independent variable; SD: standard deviation; Experimental: hAEC administration group; and Control: saline control group.

Fig 3

Funnel Plots of Ashcroft Scores (A) and Lung Collagen Contents (B). SE: standard error; and SMD: standard mean difference.

Fig 4

Egger’s Plots of Ashcroft Scores (A) and Lung Collagen Contents (B).