| BACKGROUND:Acute lung injury (ALI) is a syndrome of rapid-onset bilateral pulmonary infiltrates of non-cardiac origin, characterized by alveolar-capillary injury, inflammation with neutrophil accumulation, and release of pro-inflammatory cytokines, and systemic and local inflammatory processes play a key detrimental role in the pathophysiology of ALI. It is known that systemic and local inflammatory processes have a mainly detrimental role in the ALI. However, little is known about endogenous counter-regulatory immune mechanisms. Until today, effective therapeutic strategy is still lacking. The advancement of stem cell technology brings about prospectives in the treatment of these disorders. The present study was designed to determine whether human umbilical cord mesenchymal stem cells (UCMSC) express interleukin-1 receptor antagonist (IL-1RA) and act on CD4+CD25+Foxp3+Treg cells, leading to an improvement of ALI. Mesenchymal stem cells, which are poorly immunogenic and have potent immunosuppressive activities, have emerged as a promising candidate for cellular therapeutics for the treatment of disorders caused by abnormal immune responses. In this study we investigated in a LPS-induced mouse ALI model whether UC-MSC could ameliorate ALI.OBJECTION:This study was designed to determine if UC-MSC transplantion could promote the recovery of acute LPS-induced ALI in BABL/c mice, and in the meantime to analyze the potential mechanisms of anti-inflammatory and anti-fibrotic.METHODS:LPS-treated ALI mice were infused with UC-MSC or vehicle control. The mice were sacrificed on day 1-3 and 5 after infusion, and their clinical and pathological conditions were evaluated by body weight, survival time and histological analysis. The expression levels of pro-inflammatory cytokine proteins such as IL-1, TNF, IFN-γand IL-10 in lung and serum were examined by ELISA. The homing of UC-MSC was studie by live in vivo imaging. In vitro experiments, the suppression of UC-MSC were analyzed by co-culturing UC-MSC and splenocytes mononuclear cells (PMCs) from ALI mice. Further studies of the inhibition of UC-MSC were carried out by co-culturing UC-MSC and splenocytes mononuclear cells from normal healthy mice with stimulated by LPS. The transwell experiments were carried out for analyzing the contact necessary. The expression of CD4+CD25+Foxp3+Treg was measured in lung sample of mononuclear cells and IL-1RA in UC-MSC by PCR.RESULTS:UC-MSC could migrate to the inflamed lung and effectively treated the mice suffering from ALI with improved clinical and pathological signs. The levels of IL-1, TNF and IFN-γwere significantly lower in the lung tissues and serum of the UC-MSC-treated mice in comparison with the vehicle treated mice. Co-culture experiments showed that UC-MSC could significantly inhibit TNF and IFN-γproduction by splenocytes mononuclear cells of the ALI mice or by those isolated from normal animals and simulated with LPS. The inhibiton of UC-MSC was not dependent of cell-cell contact. The expression of CD4+CD25+Foxp3+Treg was improved in UC-MSC treated mice or in mononuclear cells after co-culturing with UC-MSC with LPS stimulation.CONCLUSION:Systemically infused UC-MSC could home to the LPS-induced inflammatory lung and effectively ameliorate ALI. One of the mechanisms of action of UC-MSC is the improvement of the CD4+CD25+Foxp3+Treg regulated inflammatory reactions involved in the pathogenesis. UC-MSC could suppress Thl cell by inhibiting the expression of transcript factor. UC-MSC could suppress IFN-γexpressing by Thl cell and TNF expressing by macrophage cell. |
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