BACKGROUND:The balance between proteinases and antiproteinases plays an important role in tissue destruction and remodelling. In chronic obstructive pulmonary disease (COPD) and emphysema, an imbalance between matrix metalloproteinases (MMPs) and inhibitors of tissue metalloproteinase (TIMPs) has been reported. Alveolar macrophages are considered to be the main source of MMPs. We therefore have analyzed the effects of free and liposomal all trans-retinoic acid (ATRA) on the expression of MMP-9 and TIMP-1 in bronchoalveolar lavage (BAL) cells from patients with COPD and patients with other lung diseases. MATERIAL AND METHODS:BAL cells were incubated 1-3 day with either liposomal or free ATRA. Supernatants were tested for MMP-9 and TIMP-1 protein in specific ELISA systems; mRNA analysis was performed by semi-quantitative RT-PCR and by quantitative LightCycler PCR. RESULTS:We demonstrate that either liposomal or free ATRA selectively down-regulates MMP-9 and up-regulates TIMP-1. At the protein level, MMP-9 is decreased 3-fold and TIMP-1 is increased 3.5-fold compared to the base line with empty liposomes or untreated cells. The ratio of MMP-9 and its inhibitor TIMP-1, which may be crucial to the overall proteolytic potential decreased by factor 8. That this countercurrent effect of ATRA is not due to an altered protein stability but to transcriptional regulation could be demonstrated by RT-PCR. Quantitative LightCycler analysis revealed a 2.5-fold decrease of MMP-9 mRNA and a 4.5 fold increase of TIMP- 1 mRNA. CONCLUSIONS:These data suggest that ATRA treatment via its impact on the proteinase/antiproteinase ratio may become a new therapeutic strategy for patients with inflammatory destructive lung diseases.

译文

背景:蛋白酶和抗蛋白酶之间的平衡在组织破坏和重塑中起着重要作用。在慢性阻塞性肺疾病(COPD)和肺气肿中,基质金属蛋白酶(MMPs)和组织金属蛋白酶抑制剂(TIMPs)之间存在失衡的报道。肺泡巨噬细胞被认为是MMP的主要来源。因此,我们分析了游离和脂质体全反式维甲酸对COPD患者和其他肺部疾病患者支气管肺泡灌洗(BAL)细胞中MMP-9和TIMP-1表达的影响。
材料与方法:将BAL细胞与脂质体或游离ATRA孵育1-3天。在特定的ELISA系统中检测上清液中的MMP-9和TIMP-1蛋白。通过半定量RT-PCR和定量LightCycler PCR进行mRNA分析。
结果:我们证明脂质体或游离ATRA选择性下调MMP-9和上调TIMP-1。与空脂质体或未经处理的细胞相比,在蛋白质水平上,MMP-9降低了3倍,TIMP-1升高了3.5倍。 MMP-9及其抑制剂TIMP-1的比例可能对总蛋白水解潜力至关重要,降低了8倍。ATRA的这种逆流作用不是由于蛋白质稳定性的改变,而是转录调控,可以通过RT证实。 -PCR。定量LightCycler分析显示MMP-9 mRNA下降了2.5倍,TIMP-1 mRNA上升了4.5倍。
结论:这些数据表明,通过对蛋白酶/抗蛋白酶比率的影响,ATRA治疗可能成为炎性破坏性肺疾病患者的一种新的治疗策略。

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