Perlmutter D H, Travis J, Punsal P I
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
J Clin Invest. 1988 Jun;81(6):1774-80. doi: 10.1172/JCI113519.
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.
中性粒细胞弹性蛋白酶是一种可降解细胞外基质多种成分的酶，其与抑制剂α1-抗胰蛋白酶（α1PI）的净平衡被认为是破坏性肺部疾病发生发展的关键决定因素，尤其是在纯合子α1PI缺乏的个体中。最近已证实在单核吞噬细胞系细胞中，包括外周血单核细胞和组织巨噬细胞，可合成和分泌α1PI。在本研究中，我们表明人类单核细胞和支气管肺泡巨噬细胞中的α1PI基因表达受一种新机制影响，即弹性蛋白酶直接调节其抑制剂的合成。在纳摩尔浓度下，中性粒细胞弹性蛋白酶或胰腺弹性蛋白酶可介导人类单核细胞和支气管肺泡巨噬细胞中α1PI mRNA稳态水平及α1PI合成速率呈剂量和时间依赖性增加。抗中性粒细胞弹性蛋白酶抗血清或用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α1PI表达的影响。弹性蛋白酶还可刺激纯合子PiZZα1PI缺乏个体单核细胞中α1PI的合成，但对分泌速率无影响；因此，该酶介导了对α1PI的一种作用，增加了抑制剂的细胞内积累，并加剧了纯合子PiZZα1PI缺乏所特有的α1PI分泌的内在缺陷。
