Elastase regulates the synthesis of its inhibitor, α1-proteinase inhibitor, and exaggerates the defect in homozygous PiZZ α1 PI deficiency

Abstract

The net balance of neutrophil elastase, an enzyme that degrades many components of the extracellular matrix, and its inhibitor, alpha-1-proteinase inhibitor (α1 PI), is thought to be a critical determinant in the development of destructive lung disease, especially in individuals with homozygous α1 PI deficiency. Synthesis and secretion of α1 PI has been recently demonstrated in cells of mononuclear phagocyte lineage, including peripheral blood monocytes and tissue macrophages. In this study we show that α1 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 α1 PI mRNA and in the rate of synthesis of α1 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 α1 PI expression. Elastase also stimulates the synthesis of α1 PI in monocytes from homozygous PiZZ α1 PI-deficient individuals, but has no effect on the rate of secretion; hence, the enzyme mediates an effect on α1 PI that increases the intracellular accumulation of inhibitor and exaggerates the intrinsic defect in secretion of α1 PI that characterizes the homozygous PiZZ α1 PI deficiency.