Elastase regulates the synthesis of its inhibitor, alpha 1-proteinase inhibitor, and exaggerates the defect in homozygous PiZZ alpha 1 PI deficiency.
Elastase regulates the synthesis of its inhibitor, alpha 1-proteinase inhibitor, and exaggerates the defect in homozygous PiZZ alpha 1 PI deficiency.
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弹性蛋白酶调节其抑制剂（α1-蛋白酶抑制剂）的合成，并夸大纯合子 PiZZ α1 PI 缺陷的缺陷。
DOI：
10.1172/jci113519
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Punsal,PI
中科院分区：
文献类型：
--
作者：
Perlmutter,DH;Travis,J;Punsal,PI
中性粒细胞弹性酶（一种降解细胞外基质许多成分的酶）及其抑制剂α -1蛋白酶抑制剂（α 1 PI）的净平衡被认为是破坏性肺部疾病发展的关键决定因素，特别是在纯合子α 1 PI缺乏的个体中。α - 1 PI的合成和分泌最近在单核吞噬细胞谱系中得到证实，包括外周血单核细胞和组织巨噬细胞。在这项研究中，我们发现α 1 PI基因在人单核细胞和支气管肺泡巨噬细胞中的表达受到一种新机制的影响，即弹性蛋白酶直接调节其抑制剂的合成。在纳摩尔浓度下，中性粒细胞或胰腺弹性蛋白酶介导α 1 PI mRNA稳态水平和α 1 PI合成速率的剂量和时间依赖性增加。中性粒细胞弹性蛋白酶抗血清或丝氨酸蛋白酶抑制剂二异丙基氟磷酸预处理弹性蛋白酶可消除弹性蛋白酶对α - 1 PI表达的影响。Elastase也刺激来自纯合子PiZZ α 1 PI缺陷个体的单核细胞α 1 PI的合成，但对分泌速率没有影响；因此，该酶介导α 1 PI的作用，增加了抑制剂在细胞内的积累，并夸大了α 1 PI分泌的内在缺陷，这是纯合子PiZZ α 1 PI缺乏症的特征。图片
The net balance of neutrophil elastase, an enzyme that degrades many components of the extracellular matrix, and its inhibitor, alpha-1-proteinase inhibitor (alpha 1 PI), is thought to be a critical determinant in the development of destructive lung disease, especially in individuals with homozygous alpha 1 PI deficiency. Synthesis and secretion of alpha 1 PI has been recently demonstrated in cells of mononuclear phagocyte lineage, including peripheral blood monocytes and tissue macrophages. In this study we show that alpha 1 PI gene expression in human monocytes and bronchoalveolar macrophages is affected by a novel mechanism, whereby elastase directly regulates the synthesis of its inhibitor. In nanomolar concentrations, neutrophil or pancreatic elastase mediates a dose- and time-dependent increase in steady state levels of alpha 1 PI mRNA and in the rate of synthesis of alpha 1 PI in human monocytes and bronchoalveolar macrophages. Antisera to neutrophil elastase or pretreatment of elastase with the serine proteinase inhibitor diisopropylfluorophosphate abrogates the effect of elastase on alpha 1 PI expression. Elastase also stimulates the synthesis of alpha 1 PI in monocytes from homozygous PiZZ alpha 1 PI-deficient individuals, but has no effect on the rate of secretion; hence, the enzyme mediates an effect on alpha 1 PI that increases the intracellular accumulation of inhibitor and exaggerates the intrinsic defect in secretion of alpha 1 PI that characterizes the homozygous PiZZ alpha 1 PI deficiency.Images