Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application

Jingtao Li,Fanpu Ji,Jie Shi,Yue Zhang,Yunyu Zhao,Ying Liu,Zhipeng Yan

doi:10.1186/s13287-021-02551-y

Abstract

Pulmonary fibrosis (PF) is a chronic, progressive, fibrotic interstitial disease of the lung with poor prognosis and without effective treatment currently. Data from previous coronavirus infections, such as the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome, as well as current clinical evidence from the Coronavirus disease 2019 (COVID-19), support that SARS-CoV-2 infection may lead to PF, seriously impacting patient prognosis and quality of life. Therefore, effective prevention and treatment of PF will improve patient prognosis and reduce the overall social and economic burdens. Stem cells, especially mesenchymal stem cells (MSCs) have many great advantages, including migration to damaged lung tissue and secretion of various paracrine factors, thereby regulating the permeability of endothelial and epithelial cells, reducing inflammatory response, promoting tissue repair and inhibiting bacterial growth. Clinical trials of MSCs for the treatment of acute lung injury, PF and severe and critically ill COVID-19 are ongoing. The purpose of this study is to systematically review preclinical studies, explored the effectiveness of MSCs in the treatment of bleomycin (BLM)-induced pulmonary fibrosis and analyze the potential mechanism, combined with clinical trials of current MSCs for idiopathic pulmonary fibrosis (IPF) and COVID-19, so as to provide support for clinical research and transformation of MSCs. Searching PubMed and Embase (− 2021.4) identified a total of 36 preclinical studies of MSCs as treatment of BLM-induced acute lung injury and PF in rodent models. Most of the studies showed the MSCs treatment to reduce BLM-induced lung tissue inflammatory response, inflammatory cell infiltration, inflammatory cytokine expression, extracellular matrix production and collagen deposition, and to improve Ashcroft score. The results of present studies indicate that MSCs may serve as a potential therapeutic modality for the treatment of PF, including viral-induced PF and IPF.

Highlights

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible condition in interstitial lung diseases (ILDs)
Inclusion criteria (a) The model of PF was induced by BLM; (b) Mice or rats were used as experimental animals, without immune deficiency or genetic modification; (c) BLM was delivered via intratracheal infusion; (d) The intervention was mesenchymal stem cells (MSCs) therapy, excluding embryonic stem cells and induced pluripotent stem cells; (e) The transplantation routes of MSCs included intratracheal infusion or intravenous injection; (f ) The study reported on original data; (g) The primary end points were pulmonary histopathological changes and quantitative or semi-quantitative analysis of the degree of pulmonary inflammation or fibrosis
Srour et al [49] later reported a retrospective analysis of 17 studies on MSCs-based treatment of BLM-induced PF in mice, showing that MSCs can improve the extent of BLM-induced pulmonary collagen deposition and reduce the Ashcroft score, decrease the total cell count, neutrophils count and Transforming growth factor-beta (TGF-β) level in bronchoalveolar lavage fluid, and improve the survival rate

Summary

Introduction

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible condition in interstitial lung diseases (ILDs). The etiology of PF is complex and related to environment, drug, pathogenesis, genetic and other factors. The etiologies vary for different pathologic forms of PF, the current hypothesis of its general pathogenesis involves abnormal wound healing of alveolar epithelial cells in response to repeated injury stimulation [2]. Injured alveolar epithelial cells secrete a variety of immune mediators, including cytokines, growth factors, and chemokines, such as TGF-β, IL-1β, IL-2, IL-6, and matrix metalloproteinases (MMPs), that alter the pulmonary microenvironment and trigger pulmonary inflammatory responses and subsequent fibrous scarring [3]. No drug is available that can reverse PF nor improve the deteriorated pulmonary function.

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