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 aim of this study was to determine whether lipopolysaccharide-induced elastase release from recruited neutrophils in the hamster lung would induce emphysema, measured by mean linear intercept (Lm) and bronchial mucus cell hyperplasia (BMCH), scored in tissue sections stained with periodic acid-Schiff. Lipopolysaccharide (LPS) was instilled transorally twice a week for up to 5 weeks in hamsters. At 4 weeks after seven LPS instillations, Lm amounted to 87.6 +/- 1.2 microns, while it was 68.3 +/- 1.5 microns after seven saline instillations (P less than 0.01). At 6 months after the sixth LPS instillation, the Lm of these lungs was 83.3 +/- 1.6 microns, indicating irreversible tissue destruction. LPS-treated hamsters showed marked to severe BMCH, which was most evident in large intrapulmonary airways. Instillations of highly selective inhibitor of hamster PMN elastase resulted in 50 per cent inhibition of LPS-induced emphysema. The development of BMCH was inhibited by approximately 35 per cent by this agent. To study the response in time of cellular infiltration after a single LPS instillation, the lungs of groups of four hamsters were lavaged at different time points. PMN recruitment showed peak values at 4 and 48 h after LPS instillation and returned to baseline values at 96 h. Simultaneous intratracheal instillation of LPS and anti-TNF alpha antiserum resulted in a considerable reduction of neutrophil influx into bronchoalveolar spaces in the first 6 h after instillation.
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PMID:Induction of emphysema and bronchial mucus cell hyperplasia by intratracheal instillation of lipopolysaccharide in the hamster. 151 4

Repeated intratracheal instillations of E. coli lipopolysaccharide (LPS) in hamster lungs cause an influx of polymorphonuclear leukocytes (PMNs) into the alveolar walls, with concomitant development of severe emphysema. It has been suggested that elastase, released by these PMNs, is involved in the development of emphysema. This study demonstrates the release of elastase from recruited PMNs in cryostat sections of hamster lungs, after being treated once, twice, or thrice with LPS, intratracheally. Elastase activity was visualized using two elastase-specific synthetic substrates, to which a methoxynaphthylamine (MNA) group had been bound covalently. Liberated MNA, when made insoluble by coupling with 5-nitrosalicylaldehyde, fluoresces strongly. The authors observed that the interval between start of incubation and appearance of fluorescence and the intensity of fluorescence correlated with the number of LPS administrations. Fluorescence was observed to be located in or in close vicinity to alveolar walls. No fluorescence was observed in sections of untreated hamsters. Liberation of MNA from synthetic substrates was delayed strongly by the addition of a recombinant secretory leukocyte proteinase inhibitor or a substituted cephalosporin neutrophil elastase inhibitor. The authors conclude that LPS-mediated PMN influx into the lung is accompanied by release of elastase from these cells and speculate that this PMN-elastase is involved in the development of LPS-mediated emphysema.
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PMID:Detection of extracellular neutrophil elastase in hamster lungs after intratracheal instillation of E. coli lipopolysaccharide using a fluorogenic, elastase-specific, synthetic substrate. 163 60

Neutrophil enzymes have been implicated as a source of lung injury in patients with the adult respiratory distress syndrome (ARDS) and with emphysema. We studied a human alveolar macrophage-derived peptide messenger, the enzyme-releasing peptide (ERP), which causes neutrophils to secrete their enzymes. The secretion and synthesis of ERP was studied in human alveolar macrophages and in the macrophage-like cell lines THP-1, HL-60, and U937. All four cell types secrete an ERP-like peptide. THP-1 cells secrete a higher concentration of the peptide than do macrophages. The secretion of ERP by THP-1 is suppressed by the protein synthesis inhibitors actinomycin D and cycloheximide. While the macrophages secrete ERP, they do not synthesize it. These studies suggest that ERP is synthesized by an alveolar macrophage precursor and stored in the mature macrophage for later release. 12-O-tetradecanoylphorbol-13-acetate (TPA) suppresses ERP secretion by THP-1 cells, but it does not modify secretion in macrophages. Escherichia coli-derived lipopolysaccharide and dimethyl sulfoxide do not modify secretion in either cell type. The THP-1 cells secrete a high- and low-mass-ratio (Mr) form of ERP-like proteins. The low Mr but not the high Mr form stimulates neutrophils to secrete their granule enzymes. We conclude that human alveolar macrophages secrete ERP but do not synthesize it. It is likely that ERP is made by an alveolar macrophage precursor in a high Mr form that is cleaved prior to secretion by the macrophages.
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PMID:Synthesis and secretion of high- and low-molecular-weight forms of the enzyme-releasing peptide (ERP) from the macrophage-like cell line THP-1. 198 75

The features of the cotton dust syndrome which need to be considered when formulating a hypothesis on mechanism(s) are: 1) the presence of fever, 2) the "Monday effect," 3) the slow onset of forced expiratory volume in 1 second (FEV1) changes, and 4) the presence of bronchitis in chronic sufferers but the absence of emphysema or fibrosis. The main hypotheses concerning the mechanisms are direct release of histamine triggered by cotton dust components, immune reactions (principally antibody mediated) to cotton dust antigens, and inflammatory response(s) triggered by endotoxins released from bacterial contaminants on the dust. While histamine release and immune reactions may occur as a result of cotton dust inhalation, it is suggested that they are of secondary importance in comparison to inflammation. Evidence is reviewed that implicates bacterial lipopolysaccharide (LPS) present in the dust as the principal etiologic agent in this process. It is postulated that LPS inhalation stimulates a secretory response by lung macrophages, involving the release of effector molecules which trigger coagulation, bronchoconstriction, fever, and mucus production. LPS-induced macrophage secretory products also promote the local sequestration and activation of both neutrophils and platelets, which serve to amplify the inflammatory response. Evidence is presented implicating both interstitial and alveolar macrophages in this process. The problems associated with the identification of "high risk" groups of cotton workers will be discussed, from a number of viewpoints; consideration will be given to the role of a variety of environmental factors (including tobacco smoking) in this context, as well as possible genetic factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Current trends in research on the etiology and pathogenesis of byssinosis. 332 57

Human neutrophil elastase is thought to play an important role in connective tissue destruction in diseases such as emphysema and arthritis. In this article, it is demonstrated that the elastase activity of mature human peripheral blood neutrophils can be rapidly increased in vitro by treatment of the cells with lipopolysaccharide from E. coli and that this increase is inhibited by corticosteroid pretreatment of the cells and by inhibitors of protein synthesis. Alterations in intracellular enzyme content of the mature polymorph in response to bacterial products or other stimuli may be important for amplification of the inflammatory response.
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PMID:Polymorphonuclear leukocyte elastase activity is increased by bacterial lipopolysaccharide: a response inhibited by glucocorticoids. 636 52

Secretory leukocyte protease inhibitor (SLPI) is a potent proteinase inhibitor produced in the lung. Stimulated neutrophils at sites of inflammation can inactivate SLPI by myeloperoxidase-mediated oxidation of the methionine residue in the active site of SLPI. Apocynin is a selective inhibitor of NADPH oxidase and may therefore protect SLPI against neutrophil-mediated oxidative inactivation. The aim of the present study was to determine the effect of apocynin on the efficacy of SLPI in preventing experimental emphysema. To investigate the effect of apocynin on emphysema without SLPI treatment, three groups of eight hamsters each received drinking water containing apocynin at concentrations of 2, 20, and 200 micrograms/ml, respectively. Emphysema was induced in these hamsters by intratracheal instillations of 500 micrograms of lipopolysaccharide (LPS) twice a week for 4 wk. In hamsters that received 200 micrograms/ml apocynin, the development of emphysema was reduced by 26.2% (p = 0.01). Other apocynin concentrations had no effect. The experiment was repeated, with SLPI added to the treatment. Of a total of six groups of hamsters, four groups (three with apocynin and one with solvent) received twice-weekly doses of a mixture of 500 micrograms of LPS and 1 mg SLPI in 200 microliters saline in the trachea for 4 wk. In addition, each LPS instillation was followed 24 and 48 h later by an instillation containing 1 mg of SLPI. Apocynin (20 and 200 micrograms/ml) improved the protective effect of SLPI from 37 to 64% and 79%, respectively (p < 0.01). We conclude that oral administration of apocynin can improve the efficacy of SLPI in preventing LPS-induced emphysema.
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PMID:Apocynin improves the efficacy of secretory leukocyte protease inhibitor in experimental emphysema. 795 25

Experiments were performed to test whether recombinant secretory leukocyte proteinase inhibitor (rSLPI) was able to prevent the development of lipopolysaccharide (LPS)-mediated pulmonary emphysema, hemorrhage, and secretory cell metaplasia (SCM) in hamsters. Several groups of eight animals were intratracheally treated for four weeks, twice a week with 0.5 mg Escherichia coli LPS or with saline. In the first experiment, an additional group of eight hamsters was treated with 0.5 mg LPS mixed with 0.5 mg rSLPI, and the animals received another instillation of 0.5 mg rSLPI 7 h later. In the second experiment, 0.5 mg LPS, mixed with 1 mg rSLPI, was given while additional instillations of 1 mg rSLPI were performed 7 h and 31 h after the first dosage. In the third experiment, 0.5 mg LPS, mixed with 0.5, 1.5, or 3.0 mg rSLPI, was given while additional instillations of 0.5, 1.5, and 3.0 mg rSLPI, respectively, were performed 24 h and 48 h after the first dosage. Hamster lungs were examined for emphysema, hemorrhage, and SCM. In all three series of experiments, we observed a significant inhibition of LPS-mediated emphysema by rSLPI. This inhibition tended to be dose related. Inconclusive results were obtained on the inhibition of LPS-mediated hemorrhage. The development of LPS-mediated SCM was not affected by rSLPI. The LPS-mediated polymorphonuclear leukocyte (PMN) influx did not change when administrations of rSLPI were given additionally. We conclude that rSLPI is able to diminish significantly the development of LPS-mediated pulmonary emphysema in hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lipopolysaccharide-induced pulmonary emphysema by intratracheally instilled recombinant secretory leukocyte proteinase inhibitor. 809 78

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

FR134043, disodium(Z,1S,15S,8S,24S,27R,29S,34S,37R)-29-ben zyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31,37 -dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,28, 31,33-octaazatetracyclo[16.13.6.1(24),(28).0(3),(8)]octatricont a-3,5,7-trien-5,6-diyl disulfate, is a water-soluble inhibitor of human neutrophil elastase with a molecular mass of 1166.15 Da. FR134043 demonstrated a characteristic competitive inhibition of human neutrophil elastase with a Ki of 8 nM. In studies using synthetic substrates, FR134043 inhibited both neutrophil elastase activity and porcine pancreatic elastase activity with IC50 values of 35 nM and 49 nM respectively. FR134043 also inhibited hydrolysis of bovine neck ligament elastin by human neutrophil elastase with an IC50 value of 210 nM. In in vivo experiments, FR134043 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage in hamsters with an ED50 value of 3.1 microg/animal for intratracheal administration and 5.0 mg/kg for intravenous administration. Subcutaneous treatment with FR134043 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice with an ED50 value of 3.3 mg/kg when evaluated 4 h after elastase injection. The potency of FR134043 given intratracheally to protect against porcine pancreatic elastase (100 microg/animal)-induced emphysema in hamsters was relatively low (Quasi-static lung compliance; ED50 = 1590 microg/animal) compared to that in acute animal models. FR134043 (10 mg/kg per h i.v. infusion) significantly improved lipopolysaccharide (0.25 mg/kg per h i.v. infusion)-induced thrombocytopenia and some coagulation parameters in rats. These results suggest that systemic administration of FR134043 would be advantageous over intratracheal administration of FR134043 for the treatment of adult respiratory distress syndrome, septic shock and pulmonary emphysema and other pathophysiologic conditions in which elastases are thought to be involved.
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PMID:Biochemical and pharmacological characterization of FR134043, a novel elastase inhibitor. 959 30

Polymorphonuclear neutrophils (PMN) have been implicated in the pathogenesis of emphysema. The chemokines interleukin-8(IL-8), growth-related oncogene (GRO-alpha) and extractable nuclear antigen (ENA)-78 may be involved in the increased numbers of PMN in smokers' airspaces. The levels of these cytokines in bronchoalveolar lavage fluid (BALF) and bronchoalveolar lavage leukocyte conditioned medium (LCM), along with BALF PMN numbers in 12 smokers who abstained for 12 h (chronic smoking) or continued to smoke until I h before study (acute smoking) and seven nonsmokers were compared. Neutrophils in BALF increased in acute (1.96+/-0.53%, 0.99+/-0.32x10(6) cells) compared with chronic smokers (0.59+/-0.25%, 0.61+/-0.24x10(6) cells, p<0.05 nonsmokers) and nonsmokers (0.79+/-0.29%, 0.05+/-0.01x 10(6) cells, p<0.05). There were no differences in IL-8 or GRO-alpha in BALF between smokers and nonsmokers. ENA-78 levels were lower in smokers (p=0.006). There was no difference in IL-8, GRO-alpha or ENA-78 in LCM from unstimulated cells in smokers versus nonsmokers. After stimulation with lipopolysaccharide (LPS) 10 ng mL(-1), IL-8 release in acute smokers (p=0.04) and GRO-alpha release in smokers (p=0.009) were significantly higher than in nonsmokers. Following stimulation with LPS 100 ng.mL(-1), GRO-alpha release was higher in smokers (p=0.03) and increased further in acute smokers (p=0.02 versus nonsmokers, p=0.04 versus chronic smokers) and ENA-78 release increased in smokers (p=0.02 versus non-smokers). In conclusion, influx of polymorphonuclear neutrophils into smokers' airspaces is an acute phenomenon and neutrophil chemokine release from mixed bronchoalveolar lavage leukocytes is influenced by cigarette smoking and endotoxins.
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PMID:Neutrophil chemokines in bronchoalveolar lavage fluid and leukocyte-conditioned medium from nonsmokers and smokers. 986 98


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