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1.
Enzymatic reduction of oxidized alpha-1-proteinase inhibitor restores biological activity. 总被引:13,自引:3,他引:10
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W R Abrams G Weinbaum L Weissbach H Weissbach N Brot 《Proceedings of the National Academy of Sciences of the United States of America》1981,78(12):7483-7486
The major serum inhibitor of proteolytic activity, alpha-1-proteinase inhibitor (alpha-1-PI), (or alpha-1-antitrypsin) can be readily inactivated by oxidation [Carp, H. & Janoff, A. (1978) Am. Rev. Resp. Dis. 118, 617-621]. This inactivation appears to be due to the oxidation of a critical methionine(s) in alpha-1-PI that is required for the inhibition of elastase activity. An enzyme from Escherichia coli that reduces methionine sulfoxide residues in protein [Brot, N., Weissbach, L., Werth, J. & Weissbach, H. (1981) Proc. Natl. Acad. Sci. USA 78, 2155-2158] can restore the biological inhibitory activity of canine oxidized alpha-1-PI. 相似文献
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Characterization of sheep alpha-1-proteinase inhibitor. Important differences from the human protein 总被引:1,自引:0,他引:1
The plasma proteinase inhibitor corresponding to alpha-1-proteinase inhibitor (alpha 1Pl) in humans was isolated from sheep plasma. Ovine alpha 1Pl is of higher molecular weight (62,000 daltons) than is human alpha 1Pl, is resistant to chemical oxidation by N-chlorosuccinimide, and has poor elastase-inactivating power compared with the corresponding inhibitor in humans. However, ovine alpha 1Pl is a potent trypsin inhibitor. Despite the differences indicated above, a partial homology (22 to 35%) exists between human and sheep alpha 1Pl, at least as analyzed through the first 20 residues of the sheep inhibitor. The weak elastase-inhibitory capacity of sheep alpha 1Pl is paralleled by the low content of elastase in the sheep neutrophil granule. These important differences between sheep and human neutrophils and plasma proteinase inhibitors should be borne in mind in designing experiments related to proteolytically mediated lung injury in the former species. 相似文献
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G D?ring 《Pediatric pulmonology》1999,28(5):363-375
Proteinase-antiproteinase imbalances are recognized in several diseases including the two most common lethal hereditary disorders of white populations, alpha(1)-antitrypsin (alpha(1)-AT) deficiency and cystic fibrosis (CF). In alpha(1)-AT deficiency, the type Z variant of alpha(1)-AT forms polymers in the endoplasmic reticulum of hepatocytes resulting in liver disease in childhood. The block in alpha(1)-AT processing in hepatocytes significantly reduces levels of circulating alpha(1)-AT. This may lead in young adults to panacinar emphysema due to insufficient protection of the lower respiratory tract from neutrophil elastase, permitting progressive destruction of the alveoli. In CF, chronic bacterial lung infections due to impaired mucociliary clearance lead to a vigorous influx of neutrophils in the airways. Released levels of neutrophil serine proteinases, particularly elastase, exceed the antiproteinase capacity of endogenous serine proteinase inhibitors in the airways. Progressive proteolytic impairment of multiple defense pathways in addition to endobronchial obstruction and airway wall destruction are thought to be responsible for the reduced life expectancy in CF patients. Strategies to augment the antiproteinase defenses in the airways of patients with severe alpha(1)-AT deficiency or CF include the intravenous or aerosol administration of serine proteinase inhibitors. Studies in both patient groups using plasma-derived or transgenic alpha(1)-AT, recombinant secretory leukoprotease inhibitor or synthetic elastase inhibitors show promising results concerning drug safety and efficacy. 相似文献
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We investigated the effect of some nonsteroidal antiinflammatory drugs (aspirin, naproxen and nimesulide) on the ability of neutrophils to oxidatively inactivate the alpha-1-proteinase inhibitor (A1PI). Nimesulide prevented the inactivation of A1PI by effectively scavenging the hypochlorous acid released by neutrophils. Aspirin and naproxen were completely ineffective. We suggest that the antiinflammatory effect of nimesulide may be due at least in part to the rescue of A1PI from neutrophil oxidative attack. The rescue of A1PI may in fact alter the elastase-A1PI balance in favor of the inhibitor, with resulting tissue protection. 相似文献
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OBJECTIVES: This study investigated (i) whether adequate concentrations of secretory leukocyte proteinase inhibitor (SLPI) in the lungs of alpha-1-antitrypsin (A1AT) deficient patients can explain the variability in the development of emphysema in these individuals, and (ii) whether cigarette smoking jeopardises the protective screen provided by functional SLPI. METHODOLOGY: Four subjects [two normal proteinase inhibitor M (PiM), two abnormal PiZ] were selected from patients presenting for diagnostic bronchoscopy and lung function testing (spirometry, DLco). Each subject underwent BAL and had blood taken for A1AT and SLPI estimation. RESULTS: As expected serum and BAL A1AT concentrations were within the normal range in the normal PiM subjects. In normal subjects, SLPI concentrations in serum and BAL were within the normal range. A1AT-deficient subjects had reduced serum and BAL levels of A1AT reflecting their genetic disorder but showed increased concentrations of SLPI in BAL and serum. Percentage neutrophil elastase (NE) inhibitory capacity of BAL fluid was low in both A1AT-deficient subjects and a cigarette-smoking normal subject. In contrast, the NE inhibitory capacity for the normal subject who had never smoked was normal. CONCLUSIONS: These findings suggest that in A1AT deficiency there may be a compensatory increase in SLPI. This may protect the lung against the development of emphysema in A1AT-deficient individuals. Cigarette smokers may have a lower SLPI concentration than non-smokers. This provides an explanation for at least some of the observed variation in the development of emphysema in A1AT deficient subjects. 相似文献
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Smoking does not reduce the functional activity of serum alpha-1-proteinase inhibitor. An epidemiologic study of 719 healthy men 总被引:2,自引:0,他引:2
J Lellouch J R Claude J P Martin G Orssaud D Zaoui J G Bieth 《The American review of respiratory disease》1985,132(4):818-820
The present study was aimed at testing the hypothesis that smoking, the major risk factor for the development of pulmonary emphysema, impairs the functional activity of alpha 1-proteinase inhibitor (alpha 1-antitrypsin). We used a population of 719 apparently healthy subjects. The serum concentrations of immunoreactive and functionally active alpha 1-proteinase inhibitor were measured by radial immunodiffusion and inhibition of porcine pancreatic elastase, respectively. Both the immunoreactive and functionally active levels of serum alpha 1-proteinase inhibitor were found to increase with tobacco consumption, but the ratio between the 2 concentrations was independent of smoking. Smoking does not, therefore, impair the functional activity of alpha1-proteinase inhibitor. 相似文献
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Expression of the alpha 1-proteinase inhibitor gene in human monocytes and macrophages. 总被引:30,自引:2,他引:28
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D H Perlmutter F S Cole P Kilbridge T H Rossing H R Colten 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(3):795-799
Expression of the alpha 1-proteinase inhibitor (alpha 1PI) gene was studied in human mononuclear cells. Using RNA blot and dot hybridization, alpha 1PI mRNA was detected in human peripheral blood monocytes, bronchoalveolar and breast milk macrophages, but not in B or T lymphocytes. Using incorporation of a radiolabeled amino acid precursor, synthesis and secretion of alpha 1PI were demonstrated in human monocytes and macrophages, but not in lymphocytes. In addition, alpha 1PI was secreted in functionally active form as shown by complexing with serine proteases. Biosynthesis of alpha 1PI by mononuclear phagocytes was greatest during the first 24 hr in culture and progressively decreased over the next 10 days. The reduction in alpha 1PI biosynthesis in vitro involved a mechanism acting at the pretranslational level as alpha 1PI mRNA content also progressively declined over 10 days in culture. The ease of sampling human monocytes and macrophages now permits examination of the biochemical defect in homozygous PiZ and PiS alpha 1PI deficiencies and study of the functional significance of locally produced alpha 1PI in normal tissues and sites of injury or inflammation. 相似文献
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Alejandro Campos-Murguía Pedro Valdéz-Hernández Jacqueline Cordova-Gallardo Jazmín Arteaga-Vázquez Alan G. Contreras Mario Vilatobá Rodrigo Cruz-Martínez Braulio Martínez-Benítez Armando Gamboa-Domínguez Braulio A. Marfil-Garza Nayelli C. Flores-García Ernesto Márquez-Guillén Ignacio García-Juárez 《Clinics and research in hepatology and gastroenterology》2021,45(4):101519
IntroductionAlpha-1 antitrypsin deficiency (AATD) is a risk factor for liver disease. PASD-positive inclusions have been found unexpectedly in approximately 10% of liver explants in patients with no previous diagnosis of AATD, particularly, in patients with non-alcoholic steatohepatitis (NASH), supporting a synergistic mechanism of liver injury between AATD and environmental factors. We aimed to determine the clinical characteristics of mestizo patients in which AATD was diagnosed before or after liver transplantation.MethodsLiver explants of patients with cryptogenic, alcoholic, and NAFLD/NASH cirrhosis undergoing orthotopic liver transplantation (OLT) were included. Liver histopathology was assessed by two expert pathologists. Hematoxylin and eosin staining, PASD staining, and confirmatory AAT immunohistochemistry were performed. In explants with positive histopathology, genotyping for SERPINA1 was performed.ResultsA total of 180 liver transplants were performed during the study period. Of these, 44 patients with cryptogenic cirrhosis, NASH, and alcoholic cirrhosis were included. Of these patients, two liver explants (4.5%) had PASD-positive inclusions stain and confirmatory immunochemistry. During the period evaluated, another two patients with a diagnosis of AATD before the OLT were also included. The four patients had overweight or obesity, three had type 2 diabetes mellitus, and two developed liver steatosis after the OLT.ConclusionAATD was found to be an infrequent finding in patients with cryptogenic, NASH/NAFLD, and alcoholic cirrhosis in our population. However, it is important to consider this entity as it may represent an additional factor in the appearance and progression of liver fibrosis in patients with metabolic syndrome. 相似文献
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Molecular characterization and phylogenetic studies of a wound-inducible proteinase inhibitor I gene in Lycopersicon species. 总被引:6,自引:6,他引:6
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J S Lee W E Brown J S Graham G Pearce E A Fox T W Dreher K G Ahern G D Pearson C A Ryan 《Proceedings of the National Academy of Sciences of the United States of America》1986,83(19):7277-7281
A gene coding for proteinase inhibitor I, whose expression is induced in tomato leaves (Lycopersicon esculentum L. var. Bonny Best) in response to wounding or insect attacks, was isolated from a genomic library and characterized. The nucleotide sequence revealed that the gene is complete and encodes the sequence of an inhibitor I cDNA that was previously isolated from a cDNA library prepared from wound-induced mRNA from tomato leaves. This gene is located 13.1 kilobase pairs (kbp) upstream from an inhibitor II gene. The wound-inducible gene is interrupted by two intervening sequences of 445 and 404 bp, situated within the codons of amino acids 17 and 47, respectively, of the open reading frame. In addition to the presence of putative regulatory sequences, TATAAA and CCACT, two copies of an imperfect direct repeat approximately 100 bp long were identified in the 5'-flanking region. Phylogenetic comparisons of wound-inducible inhibitor I genes within the genomes of various Lycopersicon species revealed that the repeat is found in seven ancestral species of tomato. 相似文献
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The cellular defect in alpha 1-proteinase inhibitor (alpha 1-PI) deficiency is expressed in human monocytes and in Xenopus oocytes injected with human liver mRNA. 总被引:19,自引:1,他引:19
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D H Perlmutter R M Kay F S Cole T H Rossing D Van Thiel H R Colten 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(20):6918-6921
To determine the basis for low serum concentrations of alpha 1-proteinase inhibitor (alpha 1PI) in individuals with homozygous alpha 1PI deficiency (hereafter referred to as PiZZ), biosynthesis and secretion of alpha 1PI were studied in Xenopus oocytes microinjected with hepatic mRNA and in blood monocytes (an extrahepatic site of alpha 1PI gene expression). Although both the usual alpha 1PI (hereafter referred to as PiMM) and PiZZ alpha 1PI were secreted in functionally active form, the rate of secretion of alpha 1PI was significantly and selectively decreased in Xenopus oocytes injected with PiZZ liver mRNA and in monocytes from PiZZ individuals. The apparent size of alpha 1PI in the intracellular compartment of Xenopus oocytes injected with PiZZ liver mRNA was different from the corresponding intracellular PiMM alpha 1PI in oocytes injected with PiMM liver mRNA. There were also differences in the relative ratio of native and complexed alpha 1PI secreted by monocytes from individuals with PiMM and PiZZ phenotypes. 相似文献
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R W Goodgame R K Bartholomew 《The American journal of tropical medicine and hygiene》1978,27(4):779-781
To evaluate the role of alpha-1-antitrypsin deficiency in the pathogenesis of hepatosplenic schistosomiasis, alpha-1-antitrypsin was measured in 90 patients with schistosomal splenomegaly and in 87 phenotyping was also done. All levels were in the normal range except for those of two patients who were shown to have the heterozygous deficiency state, PiMZ. The phenotypes found in the 87 were as would be expected in a normal population. Alpha-1-antitrypsin deficiency does not play a significant role in the pathogenesis of hepatosplenic schistosomiasis. 相似文献
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Inhibition of tumor-cell-mediated extracellular matrix destruction by a fibroblast proteinase inhibitor, protease nexin I. 总被引:21,自引:3,他引:18
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B L Bergman R W Scott A Bajpai S Watts J B Baker 《Proceedings of the National Academy of Sciences of the United States of America》1986,83(4):996-1000
Human fibrosarcoma (HT-1080) cells, in contrast to normal fibroblasts, rapidly hydrolyze the glycoprotein, collagen, and elastin extracellular matrix (ECM) synthesized by cultured rat aortic smooth muscle cells. This degradation occurs at a rapid rate in the presence of serum, indicating that the cellular proteases responsible are relatively insensitive to serum proteinase inhibitors. Here it is shown that protease nexin I (PNI), a fibroblast-secreted inhibitor of urokinase, plasmin, and certain other serine proteinases, effectively inhibited the HT-1080 cell-mediated degradation of this ECM. PNI at 2.0 nM significantly inhibited matrix destruction for 1-2 days and at 0.2 microM caused a virtually complete inhibition that persisted for the entire 10-day period of observation. Inhibition of ECM destruction was accompanied by a transient arrest of HT-1080 cell proliferation that took place during the first 3 days after PNI addition. PNI did not inhibit the growth of normal fibroblasts and also did not inhibit the growth of HT-1080 cells that were seeded onto plastic dishes rather than onto ECM. Like many types of malignant cells, HT-1080 cells release large amounts of urokinase. Antibody against this plasminogen activator partially protected ECM from HT-1080 cell-mediated hydrolysis, indicating that it may have been a target of PNI. One potential physiological function of PNI could be to help maintain the integrity of connective tissue matrices, protection that malignant cells could overcome by secreting proteinases in excessive amounts. 相似文献
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A case of acquired C1INH deficiency with angioedema is described. Fifteen cases are thus far recorded. The clinical syndrome of angioedema in these patients closely resembles hereditary angioedema (HAE). Most cases are associated with a paraprotein, cryoglobulin, or autoantibody, which presumably initiates C1 activation and C1 Inhibitor consumption. C1INH, C4 and C2 levels are low in acquired C1INH deficiency, as in HAE. A distinguishing feature is that C1 titers are very low in the acquired disease and only minimally depressed, if at all, in HAE. Most cases have appeared in patients with an underlying lymphoproliferative or autoimmune disease. Therapy is directed at the underlying disorder, but androgen therapy may be helpful in preventing attacks. Future potential therapeutic approaches are discussed. 相似文献