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)

Recent evidence suggests that connective tissue breakdown in the human lung leading to airway obstruction and emphysema involves proteinases expressed by neutrophils and macrophages that traffic to the lungs in response to cigarette smoke. It remains unclear why only a small fraction of all cigarette smokers develop symptomatic airway obstruction. In this study, we examined indexes of inflammation and proteolytic activity in samples of bronchoalveolar lavage from young cigarette smokers and questioned whether there was any correlation between the extent of inflammation or enzymatic activity and lung function. A total of 125 apparently healthy community volunteers who currently smoked at least one pack per day were evaluated by spirometry. Seven subjects with a relatively low FEV1/FVC (% predicted) were identified and further studied by bronchoalveolar lavage. These were compared with a group of 10 smokers of similar age (mean age, 33 yr) and pack-years and higher FEV1/FVC (% predicted). Both groups showed increased accumulation of lung macrophages and neutrophils as compared to nonsmokers, but there were no differences in total cells or cellular differentials between the groups. Similarly, there were no differences in either alveolar fluid phase elastase, antielastase, and plasminogen activator (PA) activities or macrophage elastolytic activity between the groups. In contrast, there was a clear difference in macrophage plasminogen activator activity between the groups, cells from the group with a lower FEV1/FVC (% predicted) having a higher PA activity than that of macrophages from the group with higher FEV1/FVC (% predicted), i.e., 0.50 +/- 0.16 international urokinase units/10(6) cells versus 0.30 +/- 0.10 units/10(6) cells (p less than 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Association between alveolar macrophage plasminogen activator activity and indices of lung function in young cigarette smokers. 320 97

Human lung macrophages express all four of the known lysosomal thiol proteases: cathepsins B, H, L, and S. These enzymes share a similar size and targeting mechanism for lysosomal accumulation and all have relatively indiscriminate substrate specificity in comparison with such highly selective serine proteases as urokinase or thrombin. These enzymes do have distinctive properties: only cathepsin B has C-terminal dipeptidase activity, only cathepsin H has potent aminopeptidase activity, and only cathepsin L and S are elastolytic. Cathepsin S is unique in that it is stable at neutral pH; indeed, at neutral pH it has elastolytic activity roughly comparable with that of neutrophil elastase. Recent studies of the differential expression of these cathepsins suggest they not only cooperate in terminal degradation of endocytized protein but also have specific functions such as proenzyme activation, antigen processing, and tissue remodeling, especially bone matrix resorption. Lysates of lung macrophages degrade elastin at neutral pH, suggesting that necrosis of macrophages at sites of macrophage accumulation, e.g., caseation necrosis, could contribute to tissue destruction. Tissue destruction and remodeling by thiol proteases expressed by live macrophages, however, is limited by tight compartmentalization of cathepsins to lysosomes. Nonetheless, macrophages accumulate at sites of known injury in cigarette smokers. Because these cells contain potent elastases, and because lysosomal enzyme release and cell surface acidification are regulated events, dysregulation of thiol protease expression in stimulated macrophages may contribute to the injury observed in cigarette smokers with non-alpha-1-protease inhibitor-type emphysema.
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PMID:The role of thiol proteases in tissue injury and remodeling. 795 52

The hypothesis, some 30 years ago, that NE was the sole proteolytic agent responsible for the development of emphysema seems naive in retrospect. The availability of technology to measure NE facilitated the early research into the relationship between NE and lung disease. Despite an abundance of information on the activity of NE in the lung, it will probably require prospective studies in man with specific NE inhibitors or control at the gene level to establish a causal relationship between NE and lung disease. Parallel research has resulted in the isolation and characterisation of NE inhibitors other than PI and, indeed, alternative proteolytic enzymes that might contribute to lung disease. It is perhaps impossible now to think that a single proteinase, however omnipotent it may be, causes lung diseases as diverse as emphysema and fibrosis. An important aspect that is emerging is the interrelationship between proteolytic enzymes produced by different, or sometimes the same, cells that could potentiate tissue proteolysis. The evidence suggests that there is likely to be coordinated action between neutrophils, macrophages, and possibly mesenchymal proteinases which can activate or inactivate each other. In addition, one class of proteinases often appears able to proteolytically inactivate inhibitors of the opposite class, which presumably could amplify proteolysis if it occurred in vivo. Although the work on this aspect of proteinase activity is in its infancy, one suspects that part of the normal regulation of proteinase activity might include compartmentalisation. For example, the neutrophil stores proteinases before appropriate release and can inactivate PI to enable proteolytic action pericellularly, whereas degradation of extracellular matrix by macrophages requires interaction between the cell and matrix which is facilitated by cell receptor bound uPA. Disintegration of these "compartments" due to oedema, proteolysis, or for mechanical reasons could, firstly, expose further extracellular matrix substrates to inflammatory and damaged cell proteinases but, secondly, might enhance proteinase potential by the cooperative action of these enzymes. It seems increasingly likely that, where proteinases play a part, there is a cocktail of proteinases that is characteristic of the injury that develops (fig). What remains unclear is why only a proportion of those susceptible, such as smokers or those with acute lung injury, develop irreversible lung disease. This suggests that there are other factors acquired or inherited that need to be considered.
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PMID:New perspectives on basic mechanisms in lung disease. 6. Proteinase imbalance: its role in lung disease. 832 46

Serine proteases are attractive targets for the design of enzyme inhibitors since they are involved in the etiology of several diseases. Within the class of serine proteases, HLE is one of the most destructive enzymes in the body. It is implicated in the promotion or exacerbation of a number of diseases including pancreatitis, acute respiratory syndrome, rheumatoid arthritis, atherosclerosis, pulmonary emphysema, and cystic fibrosis. Thrombin, a trypsin-like serine protease, plays a dual role in thrombogenesis, including fibrin formation and platelet activation. As a result, thrombin constitutes one of the most widely studied targets for antithrombotic strategy. Numerous inhibitors of serine proteases have been reported during the past three decades. Among them, coumarin-type molecules displayed a high inhibitory potency towards various serine proteases. At that time, halomethyl dihydrocoumarins have been shown to behave as the first general suicide inhibitors of serine protease. These molecules inhibit several proteases such as human leucocyte elastase, porcine pancreatic elastase, thrombin, urokinase and human plasmin. Isocoumarins are very effective as mechanism-based inhibitors of serine proteases. Pharmacomodulation on the 3-alkoxy-4-chloroisocoumarins and the 3-alkoxy-7-amino-4-chloroisocoumarins led to strong inhibitors of numerous serine proteases such as HLE, human factor XIa and XIIa, thrombin, urokinase and kallikrein. Recently, a series of coumarins characterised by an alkyl, aryl ester, amide, thioester or ketone in the position 3 and an electrophilic chloromethyl moiety in the position 6 have been developed. These compounds were found to be high inhibitors of alpha-chymotrypin, HLE and human thrombin.
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PMID:Coumarin and isocoumarin as serine protease inhibitors. 1557 71