VEGF介导p38 MAPK通路重塑肺泡壁的机制研究OA

Objective To explore the mechanism by which vascular endothelial growth factor(VEGF)mediates alveolar wall remodeling through the p38 mitogen-activated protein kinase(MAPK)signaling pathway and to determine its potential role in lung diseases.Methods Human pulmonary alveolar epithelial cells(HPAEpiCs)were treated with different doses of VEGF(2.5,5,10,20,and 40 ng/mL).Cell viability was assessed using the CCK-8 assay.Cell apoptosis and extracellular matrix protein levels were detected by immunofluorescence.The mRNA levels of p38 MAPK,ERK,and JNK were analyzed by reverse transcription-quantitative PCR.A mouse model of pulmonary fibrosis was established using bleomycin,and the mice were subsequently treated with VEGF.The hydroxyproline content in lung tissues was measured,lung tissue structure was observed using HE and Masson's staining,and the protein levels of p38 MAPK,ERK,and JNK were analyzed by Western blot.Results In the cell experiments,medium and high doses of VEGF treatment significantly inhibited the viability of HPAEpiC cells(P＜0.01,P＜0.001);after low,medium,and high doses of VEGF treatment,the expression of Caspase-3 protein in HPAEpiC cells significantly increased(P＜0.05,P＜0.05,P＜0.001),the expression of Collagen protein significantly increased(P＜0.05,P＜0.01,P＜0.001),the expression of Elastin protein significantly increased(P＜0.05,P＜0.001,P＜0.001),while the expression of E-cadherin protein significantly decreased(P＜0.05,P＜0.001,P＜0.001).After high-dose VEGF treatment,the intervention with p38 MAPK pathway inhibitor significantly reduced the expression of Caspase-3,Collagen,and Elastin proteins(P＜0.001,P＜0.001,P＜0.001),and the expression of E-cadherin protein significantly increased(P＜0.01);low,medium,and high doses of VEGF intervention could all up-regulate the mRNA levels of p38 MAPK,ERK,and JNK in cells(P＜0.05,P＜0.001,P＜0.001),while the intervention with p38 MAPK pathway inhibitor could down-regulate the mRNA expression of p38 MAPK,ERK,and JNK(P＜0.001,P＜0.001,P＜0.001).In the mouse experiments,VEGF treatment could aggravate the degree of pulmonary fibrosis in mice and significantly increase the content of hydroxyproline(P＜0.001),while the p38 MAPK pathway inhibitor significantly reduced the content of hydroxyproline(P＜0.01);VEGF intervention could also enhance the protein expression of p-p38 MAPK,ERK,and JNK in mouse lung tissue(P＜0.01,P＜0.01,P＜0.05),and the p38 MAPK pathway inhibitor could inhibit the protein expression of p-p38 MAPK,ERK,and JNK(P＜0.01,P＜0.05,P＜0.05).Conclusions VEGF may regulate the synthesis of extracellular matrix proteins in alveolar walls and promote alveolar wall remodeling by activating the p38 MAPK signaling pathway.