Therapeutic Effects Of Mesenchymal Stem Cells For Acute Lung Injury: Systematic Review With Meta-analyses Of Rat/Mouse Models

Objective To systematically review the evidence of therapeuticeffects of mesenchymal stem cells for acute lung injury in rat/mousemodels.Methods Databases (PubMed, EMbase, CENTRAL, Web ofScience) were searched for collecting the randomized controlledtrials(RCTs) on the effects of mesenchymal stem cells for acute lung injuryin rat/mouse models from inception to March,2014. We performed asystematic review with quantitative syntheses to assess the evidence ofMSCs versus controls for acute lung injury in rat/mouse models.Meta-analysis was then performed using RevMan5.2software.Results(1)13eligible controlled studies were identified comprising a total of1,148rats/mice. Between-study heterogeneity was large. Controlled studiesassessing the administration (intratracheal, oropharyngeal aspiration,intravenous, intraperitoneal, intrapleural) of MSCs isolated from specifictissues to rats/mice with ALI induced by LPS. Control interventionsconsisted of placebo (saline, PBS). Results of meta-analysis showed that,compared with controlled group, administration of MSC improved survival in an endotoxin model of ALI [OR=4.52,95%CI(2.22,9.21),P=0.95], as well as lung injury score, neutrophil counts in BALF,lung wet/dry ratio, total protein in BALF.(2) Administration of MSCs reduced the expression ofpro-inflammatory cytokines MIP-2, TNF-α, IFN-α, IL-1α, IL-1β in theBALF, while up-regulating the anti-inflammatory cytokine IL-10, andsignificant difference was found between the MSCs group and the controlgroup.Conclusion(1) Administration of MSCs significantly attenuated lung injury,reduced pulmonary edema and improved survival in ALI rats/mice.(2) MSCs administration resulted in a down-regulation ofpro-inflammatory response to endotoxin by reducing MIP-2, TNF-α,IFN-α, IL-1α, IL-1β in the BALF, while up-regulating theanti-inflammatory cytokine IL-10in the BALF, which indicated that MSCsmight partially involve modulation imbalance between pro-cytokines andanti-cytokines in alveolar spaces. The beneficial effect of MSC wasindependent of the ability of the cells to engraft in the lung.(3) Based on the current evidence, treatment with MSCs markedlydecreases the severity of LPS-induced acute lung injury and improvessurvival in rats/mice, however, the animal results should be interpreted withcaution concerning the internal and external validity of the studies inrelation to the design of future clinical trials.