Mechanistic study on the synergistic effect of Tanshinone Ⅱa and umbilical cord mesenchymal stem cells in atten-uating pulmonary fibrosis via the NRF2/HO-1 signaling pathway
SHU Ming-hui
ZHI Yao-feng
TANG Pin-sheng
ZHAO Xu-lin
LING Jie
ZUO Wan-li
Abstract：Objective To investigate the therapeutic effects and mechanisms of Tanshinone ⅡA in combination with umbilical cord mesenchymal stem cells(UCMSCs)on pulmonary fibrosis.Methods Sixty Sprague-Dawley rats were randomly assigned to the blank control group,model group,Tanshinone group,UCMSC group,and combination therapy group.Pulmonary fibrosis was induced via tracheal instillation of bleomycin.Lung tissue samples were collected on days 8 and 29 post-modeling for histological assessment of inflammation and fibrosis.Serum levels of IL-1β,MDA,and SOD,as well as lung tissue levels of HO-1,NRF2,TGF-β1,and FN1 proteins were measured.Additionally,in vitro experiments evaluated the anti-apoptotic effects of Tanshinone ⅡA on UCMSCs under hypoxic,nutrient-deprived,and toxic conditions.Results Inflammation markers:On day 8,serum IL-1βwas significantly lower in the combination group[(60.72±5.29)ng/L]than in the model group[(70.65±7.42)ng/L](P＜0.05);by day 29,both the con-trol group[(39.20±5.97)ng/L]and combination group[(38.85±4.82)ng/L]showed significantly lower IL-1βthan the model group[(48.91±5.60)ng/L](P＜0.05).Oxidative stress indicators:On day 8,SOD activity was sig-nificantly lower in the model[(37.98±5.00)ng/L]and UCMSC[(42.44±5.07)ng/L]groups compared to the con-trol group[(57.43±6.17)ng/L](P＜0.05).Tanshinone[(53.19±6.20)ng/L]and combination[(54.43±6.62)ng/L]groups showed significantly higher SOD activity than the model and UCMSC groups(P＜0.05).All treat-ment groups had significantly lower MDA levels than the model group(P＜0.05),with no significant differences among treatment groups(P＞0.05).Oxidative stress proteins:On day 8,NRF2 levels in lung tissue were significantly elevated in all treatment groups compared to the model group(P＜0.01);HO-1 levels were significantly higher in the UCMSC and combination groups than in the model group(P＜0.05).On day 29,both NRF2 and HO-1 levels remained signifi-cantly elevated in the UCMSC and combination groups(P＜0.05).Fibrosis-related proteins:On day 8,all modeled groups showed significantly increased FN1 and TGF-β1 levels compared to controls(P＜0.001).Treatment groups had significantly lower TGF-β1(P＜0.01)but not FN1 levels(P＞0.05)compared to the model group.On day 29,all treatment groups showed reduced FN1 levels compared to the model group(P＜0.001),with the combination group show-ing significantly lower FN1 levels than the Tanshinone group(P＜0.05).TGF-β1 levels were significantly lower in all treatment groups(P＜0.05),and levels in the combination group were comparable to controls(P＞0.05).In vitro re-sults:Tanshinone ⅡA significantly reduced UCMSC apoptosis under hypoxic,nutrient-deficient,and toxic conditions(P＜0.05).Conclusion Tanshinone ⅡA synergizes with UCMSCs to ameliorate bleomycin-induced pulmonary fibro-sis in rats more effectively than either treatment alone.This effect may be attributed to Tanshinone ⅡA's ability to prolong UCMSC survival and activate multiple antioxidative pathways,thereby reducing fibrosis progression.
Keywords：Tanshinone ⅡApulmonary fibrosisoxidative stressmesenchymal stem cells
Publication Date：2025-07-15
Online Publishing Date：2025-08-25(First online date of this platform, not the publication date of the document)
Pages：9( 961-969 )