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)

The importance of proteases and protease inhibitors for the pathogenesis of pulmonary emphysema and chronic bronchitis of the horse is described. Endogenous elastases from neutrophil granulocytes and macrophages, which probably provoke emphysema in the human being, are not relevant in horse emphysema. Exogenous elastases from different species of streptomyces may be responsible for emphysema generation in this species. Part of the exogenous elastases are poorly or not inhibited at all by the equine blood protease inhibitors especially by alpha 1-protease inhibitors. A disorder similar to genetic alpha 1-protease inhibitor deficiency in the human being could not be found in the horse. Proteases and protease inhibitors are probably also relevant for the pathogenesis of chronic bronchitis. Neutral proteases from neutrophil granulocytes may be relevant as initiators or amplifiers of an inflammation in the human being and in the horse. Under physiological conditions the proteases are controlled by the secretory protease inhibitor called HUSI-1 in the human being. In contrast, the horse lacks a protease inhibitor proper to secretion in its respiratory ducts. Protease activity, which correlates with the degree of the COPD, was detected in equine inflamed tracheobronchial secretions. This finding is useful in diagnostic evaluation of the individual disease.
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PMID:[Proteases and protease inhibitors of possible clinical relevance in COPD of horses]. 332

Secretory leukocyte inhibitor (SLPI) is a potent inhibitor of serine proteinases, but sensitive to oxidative inactivation due to a methionine residue in the active centre of the inhibitor. We compared the potency of an oxidation-resistant mutant of recombinant SLPI with native recombinant SLPI in lipopolysaccharide (LPS)-induced emphysema in the hamster. Application of this oxidation-resistant mutant reduced the induced emphysema by 70 and 85% in two separate series of experiments. In contrast, an equal amount of native rSLPI resulted in significantly lower inhibition, 30 and 23%, respectively (P = 0.002). To demonstrate the effect of oxygen radicals upon a single LPS instillation in the lungs, we measured anti-neutrophil elastase activity in lung lavage fluid at 10 and 24 h after the instillation of a mixture of LPS and native rSLPI. We found that residual native rSLPI was only 70 and 55% active, respectively. The rSLPI-mutant remained 93% active in a similar experiment. The native and mutant inhibitor showed equal potency against proteinases in a granule extract of hamster neutrophils. We conclude that the replacement of methionine by leucine in the inhibitory centre of rSLPI results in a decreased sensitivity to oxidative inactivation and that this alone is sufficient to explain the greater efficiency of the rSLPI-mutant in reducing the extent of LPS-induced emphysema.
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PMID:Potency of an oxidation-resistant mutant of secretory leukocyte proteinase inhibitor in lipopolysaccharide-induced emphysema in hamsters. 809 18

Native antileukoproteinase (ALP) and two oxidant resistant mutants ALP 242 and ALP 231 were synthesized by means of recombinant DNA technology. In the ALP 242 molecule the methionine residue located in the reactive centre of the binding loop is replaced by a leucine residue. In ALP 231 all four methionine residues of the second domain were substituted by leucine residues. The native inhibitor and the two oxidant resistant molecules show comparable inhibitory capacities towards human neutrophil elastase (HLE) and cathepsin G. All three inhibitors were treated with different reactive oxygen species. After incubation with chloramine T or supernatants of activated polymorphonuclear leukocytes (PMN's) a drastic drop of inhibitory capacity of the native molecule was observed. Compared to the native form of ALP the mutant ALP 242 was less inactivated, whereas ALP 231 was nearly totally resistant towards all reactive oxygen. (Heinzel-Wieland R. et al., Biomed Biochim Acta 50: 677-681 (1991)) The intratracheal administration of HLE into the lung of Syrian Hamsters induced mild to moderate emphysematous lesions. The inhibitory potencies of native ALP and the ALP mutants were determined in this animal model by means of intratracheal instillation of the different molecules one hour prior to the administration of HLE. The inhibitory effects of ALP 242 and ALP 231 towards HLE-induced emphysema were significantly better than that of the native molecule. Surprisingly no significant differences between the two mutants were observed. (Rudolphus A. et al., Clin Sci 81: 777-784 (1991)) In a second animal model the emphysema was induced by repeated intratracheal administration of lipopolysaccharides (LPS) into the hamster lungs. This model is characterized by a chronic process of inflammation probably caused by a continuous release of endogenous elastase from infiltrating PMN's. Repeated applications of 1 mg of ALP 242 reduced the LPS-induced emphysema by 70 to 80%. In contrast, equal amounts of the native molecule resulted in significantly lower inhibition of the LPS-induced emphysema, only 23-30% reduction was observed. Repeated applications of 1 mg of ALP 231 reduced the LPS-induced emphysema only about 50%. So far it is not yet clear, why the totally oxidant resistant ALP 231 was less effective than the ALP 242 molecule. (Stolk J. et al., Pulmonary Pharmacology in press (1992))
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PMID:Oxidation resistant muteins of antileukoproteinase as potential therapeutic agents. 835 18

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.
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PMID:Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). 1058 15

Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke (CS)-induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after CS-exposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice. This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti-oxidant balance, but also inflammation and the protease/anti-protease balance.
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PMID:Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. 1632 49