alpha 1 Proteinase inhibitor (PI) is the principle inhibitor of neutrophil elastase, an enzyme that degrades many components of the extracellular matrix. Expression and regulation of alpha 1 PI, therefore, affects the delicate balance of elastase and antielastase, which is critical to turnover of connective tissue during homeostasis, tissue injury, and repair. In this study we show that expression of alpha 1 PI in human monocytes and macrophages is regulated during activation by LPS. LPS mediates a concentration- and time-dependent increase in the rate of synthesis of alpha 1 PI in mononuclear phagocytes. There is a 4.5-8.7-fold increase in functionally active inhibitor delivered to the cell culture fluid of monocytes. The effect of LPS is specific in that it is neutralized by an mAb to the lipid A moiety. The increase in expression of alpha 1 PI mediated by LPS occurs in the context of other specific changes in the expression of serine proteinase inhibitor genes in mononuclear phagocytes. There is an increase in the rate of synthesis of C1 inhibitor and a decrease in synthesis of alpha 2 macroglobulin. Regulation of alpha 1 PI by LPS is distinctive in that it is largely determined by a change in the efficiency of translation of alpha 1 PI mRNA. LPS has no effect on the rate of posttranslational processing and/or secretion of alpha 1 PI and, therein, causes greater intracellular accumulation of alpha 1 PI in mononuclear phagocytes from individuals with homozygous PiZZ alpha 1 PI deficiency.
Proteolytic cleavage of influenza virus hemagglutinin (HA) glycoprotein into subunits designated HA1 and HA2 is required for penetration of virus into the cell. It is generally assumed that this cleavage is an intracellular function of the host cell. Human adenoid fibroblast (HAF) lines, which support the growth of influenza A virus but release virus with an uncleaved HA, provide a model system that has allowed exploration of mechanisms of cleavage in vivo. Exposure of HAF-grown influenza virus to nasal secretions from children with respiratory tract symptoms induced HA cleavage and rendered virus fully infectious. Characterization of this proteolytic enzyme, present in the extracellular environment of the respiratory tract, suggests that it is a serine endopeptidase.
ABSTRACT. The net balance of neutrophil elastase and its inhibitor, a,-antitrypsin (al-AT), is a critical determinant of connective tissue turnover during homeostasis and in disease states. In addition to liver-derived a,-AT, which translocates from blood to tissues, this elastase-a,-AT balance is maintained by expression of al-AT at the local tissue level in resident mononuclear phagocytes. Our previous studies have shown that this elastase-al-AT balance is also tightly controlled at a cellular level in that addition of exogenous neutrophil elastase (serpine-type elastase) to cultured mononuclear phagocytes is associated with an increase in expression of the al-AT gene. Subsequent studies have demonstrated that this novel regulatory loop involves interaction between exogenous neutrophil elastase and endogenous a,-AT inducing a structural rearrangement in the al-AT molecule and exposing highly conserved conformation-specific domain of a,-AT, which can then be recognized by a specific cell surface receptor, the serpinenzyme complex receptor. In the following study, we examined the effect of a bacterial metalloelastase, Pseudomonas aeruginosa elastase, on expression of a,-AT in human mononuclear phagocytes. We show that pseudomonas elastase inactivates monocyte-derived a,-AT by limited proteolysis but, in so doing, a,-AT becomes recognized by the serpin-enzyme complex receptor and mediates an increase in de novo synthesis of a,-AT in these cells. However, the concentrations of pseudomonas elastase needed to proteolytically inactivate al-AT in monocyte culture fluid are higher than those required for inactivation of purified plasma a,-AT. Results of experiments in this report show that this can be explained, at least in part, by binding of pseudomonas elastase to another endogenous protease inhibitor, a2-macroglobulin. Thus, the results of this study further define the elaborate mechanisms by which the host mononuclear phagocyte controls the elastase-a,-AT balance and, in turn, connective tissue turnover. (Pediatr Res 29: 133-140,1991) Abbreviations a,-AT, a,-antitrypsin LPS, lipopolysaccharide SEC, serpin-enzyme complex
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.