Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolytic enzymes play an important role during remodeling and digestion of extracellular matrix proteins. An overproduction of extracellular matrix or insufficient extracellular matrix digestion may result in fibrosis. Enhanced proteolytic activity or an insufficient inhibitory potential could be followed by emphysema development. Since the first reports showed an emphysema induction in rats after intratracheal application of the cysteine protease papain, a number of proteolytic enzymes involved in the remodeling of the extracellular matrix of the lung were discovered. Most of them are cysteine-, metallo-, serine- or aspartic proteases. In this paper some new findings concerning the expression, function and regulation of the activity of papain-like cysteine proteases in the process of tissue destruction and remodeling in the lung are reviewed. The functional relationship between cathepsins and other proteolytic enzymes are discussed.
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PMID:[Cathepsin cysteine proteinases in the lung]. 1048 79

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.
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PMID:Serine proteinase inhibitor therapy in alpha(1)-antitrypsin inhibitor deficiency and cystic fibrosis. 1053 68

Recent studies have suggested that macrophage-derived metalloproteases are the critical mediators of cigarette smoke-induced emphysema, in contrast to earlier hypotheses that this process was mediated by neutrophil elastase. To determine whether smoke can acutely induce connective tissue breakdown in the lung and to examine the mediators of this process, we exposed C57-BL/6 mice to whole cigarette smoke and used high-performance liquid chromatography to examine lavage fluid levels of desmosine (DES), a marker of elastin breakdown, and hydroxyproline (HP), a marker of collagen breakdown. Smoke produced a dose-response increase in lavage neutrophils, DES, and HP, but not lavage macrophages (MACs). This effect was evident by 6 h after exposure to two cigarettes. Pretreatment with an antibody against polymorphonuclear leukocytes (PMNs) reduced lavage PMNs to undetectable levels after smoke exposure, did not affect MAC numbers, and prevented increases in lavage DES and HP. Intraperitoneal injection of a commercial human alpha1-antitrypsin (alpha1AT) 24 h before smoke exposure increased serum alpha1AT levels approximately 3-fold and completely abolished smoke-induced connective tissue breakdown as well as the increase in lavage PMNs, again without affecting MAC numbers. We conclude that in this model cigarette smoke can acutely induce connective tissue breakdown and that this effect is mediated by neutrophil-derived serine proteases, most likely neutrophil elastase. Exogenous alpha1AT is protective and appears to inhibit both matrix degradation and PMN influx, suggesting that alpha1AT has anti-inflammatory as well as antiproteolytic effects in this system.
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PMID:Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by alpha1-antitrypsin. 1065 46

Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A beta-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin alpha1-antitrypsin to 2 A resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease.
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PMID:Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease. 1093 92

Alpha1-antitrypsin (alpha1-AT) is the most abundant circulating inhibitor of serine proteases and therefore is essential to normal protease-anti-protease homeostasis. Inheritance of two parental alpha1-AT deficiency alleles is associated with a substantially increased risk for development of emphysema and liver disease. In very rare circumstances individuals may inherit alpha1-AT null alleles. Null alpha1-AT alleles are characterized by the total absence of serum alpha1-AT. These alleles represent the extreme end in a continuum of alleles associated with alpha1-AT deficiency. The molecular mechanisms responsible for absence of serum alpha1-AT include splicing abnormalities, deletion of alpha1-AT coding exons and premature stop codons. While these alleles comprise only a small proportion of alpha1-AT alleles associated with profound alpha1-AT deficiency, studies of their molecular mechanisms provide valuable insights into the structure, gene expression and intracellular transport of alpha1-AT.
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PMID:Molecular mechanisms of alpha1-antitrypsin null alleles. 1095 48

Alpha1-antitrypsin (alpha1AT) deficiency is a common lethal hereditary disorder of white persons of European descent. The condition is characterized by reduced serum levels of alpha1AT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. Alpha1AT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase cathepsin G and proteinase 3. The clinical manifestations of alpha1AT deficiency occur chiefly in the lung, with a high risk of emphysema occurring by the third or fourth decade of life. Cigarette smoking accelerates the development of emphysema in persons with alpha1AT deficiency. There is also an increased risk of liver disease in alpha1AT deficiency, which occurs mostly in childhood. In this review, we will define further the diagnosis of alpha1AT deficiency and its clinical manifestations and describe the therapeutic strategies that are currently being developed to treat the hepatic and pulmonary disease associated with this condition.
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PMID:Alpha1-antitrypsin deficiency: biological answers to clinical questions. 1120 78

Serine proteinase inhibitors (Serpins) are irreversible suicide inhibitors of proteases that regulate diverse physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, neoplasia and viral pathogenesis. The molecular structure and physical properties of serpins permit these proteins to adopt a number of variant conformations under physiological conditions including the native inhibitory form and several inactive, non-inhibitory forms, such as complexes with protease or other ligands, cleaved, polymerised and oxidised. Alterations of a serpin which affect its structure and/or secretion and thus reduce its functional levels may result in pathology. Serpin dysfunction has been implicated in thrombosis, emphysema, liver cirrhosis, immune hypersensitivity and mental disorders. The loss of inhibitory activity of serpins necessarily results in an imbalance between proteases and their inhibitors, but it may also have other physiological effects through the generation of abnormal concentrations of modified, non-inhibitory forms of serpins. Although these forms of inhibitory serpins are detected in tissues and fluids recovered from inflammatory sites, the important questions of which conditions result in generation of different molecular forms of serpins, what biological function these forms have, and which of them are directly linked to pathologies and/or may be useful markers for characterisation of disease states, remain to be answered. Elucidation of the biological activities of non-inhibitory forms of serpins may provide useful insights into the pathogenesis of diseases and suggest new therapeutic strategies.
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PMID:Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. 1127 63

A number of serine proteases, matrix metalloproteases, and cysteine proteases were evaluated for their ability to cleave and inactivate the antiprotease, secretory leucoprotease inhibitor (SLPI). None of the serine proteases or the matrix metalloproteases examined cleaved the SLPI protein. However, incubation with cathepsins B, L, and S resulted in the cleavage and inactivation of SLPI. All three cathepsins initially cleaved SLPI between residues Thr(67) and Tyr(68). The proteolytic cleavage of SLPI by all three cathepsins resulted in the loss of the active site of SLPI and the inactivation of SLPI anti-neutrophil elastase capacity. Cleavage and inactivation were catalytic with respect to the cathepsins, so that the majority of a 400-fold excess of SLPI was inactivated within 15 min by cathepsins L and S. Analysis of epithelial lining fluid samples from individuals with emphysema indicated the presence of cleaved SLPI in these samples whereas only intact SLPI was observed in control epithelial lining fluid samples. Active cathepsin L was shown to be present in emphysema epithelial lining fluid and inhibition of this protease prevented the cleavage of recombinant SLPI added to emphysema epithelial lining fluid. Taken together with previous data that demonstrates that cathepsin L inactivates alpha(1)-antitrypsin, these findings indicate the involvement of cathepsins in the diminution of the lung antiprotease screen possibly leading to lung destruction in emphysema.
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PMID:Cathepsin B, L, and S cleave and inactivate secretory leucoprotease inhibitor. 1143 27

The serine proteinase elastase is located in the azurophil granules of mature circulating polymorphonuclear neutrophils. This neutrophil elastase or NE is a potent non specific serine protease which plays a role as bactericidal agent and in the degradation of immune complexes by intraphagosomal processes. It promotes inflammation when the granule contents are secreted in the extracellular environment. In certain pathological circumstances, an imbalance between NE and its major plasmatic inhibitor alpha 1-PI (formerly, alpha 1-antitrypsin) leads to abnormal tissue destruction and disease development. Genetic or acquired alpha 1-PI deficiency is thought to be involved in the pathogenesis of pulmonary emphysema. A variety of degenerative and degradative disorders are also associated to uncontrolled proteolysis by NE (rheumatoid arthritis, glomerulonephritis, adult respiratory distress symptom, psoriasis, cancer). Numerous inhibitors of NE have been reported. Various molecules are currently undergoing clinical trials for emphysema and other pulmonary diseases.
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PMID:[Elastase inhibitors]. 1172 26

Elastases are proteinases capable of solubilizing fibrous elastin. They may belong to the class of serine proteinases, cysteine proteinases and metalloproteinases. Mammalian elastases occur mainly in the pancreas and the phagocytes. Among non-mammalian elastases there is a great variety of bacterial metallo and serine elastases. The elastolytic activity varies from one elastase to another and is usually not correlated with the catalytic efficiency of these proteinases. One may measure this activity using native or labelled elastins. With pure elastases one may use synthetic substrates. There is a large number of natural (proteins) and synthetic elastase inhibitors. Elastases play a pathologic role in pulmonary emphysema, cystic fibrosis, infections, inflammation and atherosclerosis.
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PMID:[The elastases]. 1172 30


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