PDTC对百草枯致肺损伤大鼠TGF-β1及MMP-2和TIMP-1表达的影响

目的 探讨四氢吡咯二硫代氨基甲酸酯(pyrrolidine Dithiocarbamate,PDTC)对百草枯(paraquat,PQ)致肺损伤大鼠转化生长因子β1(TGF-β1)、基质金属蛋白酶(MMP-2)和基质金属蛋白酶组织抑制剂(TIMP-1)表达的影响.方法 54只SD大鼠随机分为对照组(生理盐水组)、单纯染毒组(4个组)和干预组(4个组).除对照组外,各组均一次性灌胃PQ40mg/kg染毒,PDTC干预组在PQ染毒后立即一次性腹腔注射PDTC 120 mg/kg.在染毒后3、7、14、21 d各取1组动物,用反转录-聚合酶链反应(RT-PCR)法及荧光定量PCR法检测肺组织中TGF-β1、MMP-2和TIMP-1基因的表达,并观察肺组织病理改变.结果 与对照组相比.染毒组大鼠血浆TGF-β1蛋白、肺组织TGF-β1、MMP-2mRNA表达随时问延长呈现先升高后降低趋势,差异有统计学意义(P<0.05或P<0.01),TIMP-1表达持续增高,差异有统计学意义(P<0.01).PDTC干预组3、14 d TGF-β1mRNA表达分别为0.54±0.08、0.72±0.04,7、14 dMMP-2 mRNA表达分别为1.62±0.50、1.97±0.34,7、21 d TIMP.1 mRNA表达分别为1.79±0.21、2.00±0.34,与单纯染毒组相比,均明显降低,差异有统计学意义(P<0.05或P<0.01).结论 PDTC对肺损伤大鼠不同时期肺组织中TGF-β1、MMP-2及TIMP-1的mRNA表达均有一定的下调作用,可能是通过减轻中毒早期炎症的损伤、调整MMPs/TIMPs间的平衡,从而延缓肺纤维化的进程.

Influence of pyrrolidine dithiocarbamate (PDTC) on expression of transforming growth factor β1, matrix metalloproteiuase-2 and tissue inhibitor-1 of metalloproteinase in rats with pulmonary damage induced by paraquat

Objective To investigate the influence of pyrrolidine dithiocarbamate (PDTC) on the expres sion of transforming growth factor β1(TGF-β1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor-1 of metalloproteinase (TIMP-1) in rats with pulmonary damage induced by paraquat (PQ). Methods Fifty-four healthy male SD rats were randomly assigned into the control group(normal saline), the PQ-treatment groups(4 groups)and the PDTC treatment groups (4 groups). Except the rats in the control group,the rats in the PQ group were garaged only with 40 mg/kg PQ, and PDTC group with 40 mg/kg PQ plus immediate injection 120 mg/kg PDTC(i.p). On the 3rd, the 7th, the 14th and 28th day after treatments, one group rats of each treatments were sacrificed and lung and blood samples were collected. The level of TGF-β1 protein in the plasma, the mRNA expression of TGF-β1,MMP-2 and TIMP-1 were evaluated using RT-PCR and real-time quantitative PCR,while pathological changes of lung were examined under optical microscope and electrical microscope. Results The TGF-β1 protein,TGF-β1 and MMP-2 mRNA expression were increased significantly in the earlier stage and then decreased after PQ administration (P<0.05 or P<0.01),while the mRNA level of TIMP-1 was augmented continuously (P<0.01) throughout the study compared to the control group. In comparison with the PQ group,in the PDTC treatment group,the TGF-β1 mRNA expression on the 3rd and the 14th day,0.54±0.08 and 0.72±0.04 respectively,the MMP-2 mRNA expression on the 7th and 14th day, 1.62±0.50 and 1.97±0.34 respectively,and the TIMP-1 mRNA on the 7th and 21st day, 1.79±0.21 and 2.00±0.34 respectively,were significantly decreased (P<0.05 or P<0.01 ). Conclusion PDTC could attenuate paraquat-induced up-regulation of TGF-β1 and its mRNA expression, MMP-2 and TIMP-1 mRNA levels,which indicates that PDTC may exert its protective effects on paraquat-induced pulmonary damage by alleviating the earlier inflammation damage and adjusting the balance between MMPs and TIMPs. However, further studies are still warranted to investigate and clarify the underlying mechanisms involved in this complicated process.