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C Vogelmeier

Publications and source records attributed to C Vogelmeier.

At least 109 records · Page 6Linked to original sources
PubMed1995

[Pathogenesis of idiopathic pulmonary fibrosis].

Idiopathic pulmonary fibrosis or lone cryptogenic fibrosing alveolitis is an interstitial lung disease of unknown origin carrying an unfavorable prognosis. A yet unidentified hazard triggers a chronic inflammatory infiltration of the lung parenchyma characterized by an accumulation of alveolar macrophages, neutrophil and eosinophil granulocytes, and lymphocytes. Cytokines released by the activated cells modulate the inflammatory events. Oxidants and proteases, mainly released by alveolar macrophages and neutrophil granulocytes, mediate the injury to the lung parenchyma, leading to loss of alveolar-capillary units. The ensuing repair process, mesenchymal cell proliferation and up-regulation of synthesis of collagen fibers and other components of connective tissue matrix, replaces lung parenchyma by fibrotic tissue, leading to irreversible pulmonary dysfunction.

Cytokines↗
PubMed1994

[Therapy of lung diseases with antiproteases].

Neutrophil elastase (NE) is the most important protease of the human lung; if not inhibited NE is able to attack nearly all structural proteins and components of the immune system of the lung. In the normal human lung this is prevented by an excess of protease inhibitors. Based on quantitative and kinetic analyses alpha 1-antitrypsin (AAT) is the most important protease inhibitor of the human lung followed by the Secretory Leukoprotease Inhibitor (SLPI). As protease inhibitors may be inactivated by proteases and reactive oxygen metabolites released from polymorphonuclear cells, it is not surprising that some lung diseases--in particular lung emphysema caused by AAT deficiency, cystic fibrosis and ARDS--are characterized by an imbalance between proteases and protease inhibitors. Because uninhibited NE seems to play an important role in the pathogenesis of these diseases, it is obvious to use protease inhibitors as drugs. Up to now in most studies in men AAT purified from human plasma has been used: worldwide a substantial number of patients with lung emphysema caused by AAT deficiency is treated continuously; in addition AAT was aerosolized to patients with cystic fibrosis in a short term study with results suggesting that this therapy is efficient at least on a biochemical basis. We performed in vitro and in vivo animal studies with the recombinant form of SLPI (rSLPI). In these experiments we found that aerosolized rSLPI a) is not altered in its form or function in the first 13 h following aerosol; b) has a half-tie of 12 h in the lung; c) reaches the interstitium of the lung in intact form.(ABSTRACT TRUNCATED AT 250 WORDS)

Endopeptidases↗
PubMed1994

[Therapy of lung diseases with anti-oxidants].

Oxidants, highly reactive free radicals, play a major role in the pathogenesis of a variety of inflammatory lung disorders. In the healthy lung, the oxidant burden is balanced by the local antioxidant defenses. However, both an increased oxidant burden and/or decreased antioxidant defenses may reverse the physiological oxidant-antioxidant balance in favour of oxidants, leading to lung injury. This concept points to an obvious therapeutic strategy: augmentation of the antioxidant screen of the lung to prevent oxidant-mediated tissue damage. Studies using reduced glutathione (GSH), the major pulmonary antioxidant, as a model therapeutic agent demonstrate that GSH can be administered directly to the respiratory epithelial surface by aerosol and is fully functional as an antioxidant both in vitro and in vivo. In pulmonary diseases such as idiopathic pulmonary fibrosis or following HIV-infection GSH aerosol therapy not only normalises deficient pre-therapy GSH-levels in the lung, but is capable of favourably influencing cellular events such as oxidant release by pulmonary inflammatory cells. These results suggest that it is possible to use antioxidants to reverse the imbalance between oxidants and antioxidants at the site of oxidant injury to prevent the progressive tissue damage in lung disorders characterised by high oxidant states.

AIDS-Related Opportunistic Infections↗
PubMed1993

Electrophoretic characterization of wheat grain allergens from different cultivars involved in bakers' asthma.

In order to identify and characterize the wheat grain allergens involved in bakers' asthma, proteins were sequentially extracted from whole-meal flour. The polypeptide composition of the individual solubility fractions (albumin/globulin, gliadin and glutenin) was analyzed by sodium dodecyl sulfate-gel electrophoresis (SDS-PAGE), and high-resolution two-dimensional gel electrophoresis with immobilized pH gradient 4-9 in the first dimension (IPG-Dalt). The resolved polypeptides were transferred onto an immobilizing polyvinylidene difluoride membrane and incubated with a pooled serum from four asthmatic bakers. Bound IgE was demonstrated by autoradiography using 125I-labeled anti-human IgE. Our study demonstrated that the serum of the bakers allergic to flour contained IgE antibodies which bound to numerous polypeptides of all three solubility fractions. The highest percentage of IgE binding was observed with certain albumin and/or globulin polypeptides, whereas the gliadins and glutenins exhibited considerably less allergenicity. SDS-PAGE revealed that the protein which bound the highest percentage of IgE from the sera of the allergic bakers is a 27 kDa albumin. More detailed investigations using IPG-Dalt demonstrated that this allergen is not a single polypeptide but consists of several polypeptide spots that differ in their isoelectric points. Quantitative studies using computer-assisted laser densitometry revealed that the amount of patients' IgE bound by these particular polypeptides differed considerably between the seven wheat cultivars examined, ranging from 13% to 53% of the total radioactive uptake.

Albumins↗
PubMed1993

Recombinant secretory leukoprotease inhibitor augments glutathione levels in lung epithelial lining fluid.

Secretory leukoprotease inhibitor (SLPI), a 12-kDa serine antiprotease, serves as the major inhibitor of neutrophil elastase (NE) on the epithelial surface of the upper airways. As a control for studies to evaluate the aerosol administration of recombinant SLPI (rSLPI) to augment the anti-NE defenses of the lung, the status of antioxidants in respiratory epithelial lining fluid (ELF) was evaluated. Unexpectedly, aerosol administration of rSLPI caused an elevation in ELF glutathione, a major component of the epithelial antioxidant screen; i.e., rSLPI may provide not only augmentation of anti-NE defenses but also antioxidant defenses. To evaluate this concept, rSLPI (100 mg) was aerosolized to sheep, and SLPI, glutathione, anti-NE capacity, and anti-H2O2 capacity were evaluated in respiratory ELF over a 30-h period. As expected, aerosolization of rSLPI increased ELF SLPI levels and anti-NE capacity. Strikingly, postaerosol levels of glutathione in ELF were also increased (5-fold 24 h after aerosol), with a concomitant increase in ELF anti-H2O2 capacity; i.e., the rSLPI augmented the antioxidant screen of ELF. This suggests that rSLPI may be particularly well suited for therapy in lung diseases characterized by excess of both serine proteases and oxidants on the respiratory epithelial surface.

Aerosols↗
PubMed1993

Activation of blood neutrophils in acute episodes of farmer's lung.

Farmer's lung often presents clinically as recurring acute episodes several hours after exposure to moldy hay. During these episodes the blood neutrophil count increases. Because activated neutrophils release toxic oxygen metabolites and proteinases, we hypothesized that the pulmonary reaction in farmer's lung may be induced by the secretory products of activated neutrophils. To evaluate this concept, we quantified the respiratory burst of separated blood neutrophils from patients with farmer's lung (n = 12) during standardized exposure tests with moldy hay. The respiratory burst of these cells was evaluated by measuring zymosan-stimulated and lucigenin-amplified chemiluminescence (CL). Asymptomatic farmers (n = 12) and normal volunteers with no prior exposure to moldy hay (n = 15) were used as control subjects. As expected, following exposure in the group of patients with farmer's lung, striking changes in VC, TLCO, and PaO2 were observed, whereas there were only minor changes in these parameters in both control groups. In all three groups a considerable increase in the blood leukocyte count was observed. The CL response of the blood neutrophils from patients with farmer's lung 6 h after exposure was significantly higher than before or 1 h after exposure (p < 0.05 for both comparisons), whereas there was no significant change in the CL response in either control group during the observation period. Our results indicate that antigen inhalation induces an increase in the number of circulating neutrophils in patients and controls, but in patients with an acute episode of farmer's lung the neutrophils are primed for an enhanced respiratory burst and may thereby damage the lung.

Acridines↗
PubMed1992

Immunophenotyping of lymphocyte subsets in bronchoalveolar lavage fluid. Comparison of flow cytometric and immunocytochemical techniques.

In order to compare flow cytometry with the conventional peroxidase anti-peroxidase method for the immunophenotyping of bronchoalveolar lavage fluid (BALF) lymphocytes, we studied BALF samples from 27 patients with various interstitial lung diseases. The results achieved with both methods were consistent concerning CD3+ pan T cells, CD4+ T helper/inducer, CD8+ T suppressor/cytotoxic and CD57+ natural killer cells. In contrast, a statistically significant lower anti-HLA-DR positive subset was obtained with flow cytometry than with the immunoperoxidase method (p less than 0.005). Since regression analyses and reliability counts showed further agreement between the methods, we conclude that flow cytometric immunophenotyping of BALF lymphocytes leads to similar, if not better, subset analyses than the immunoperoxidase method.

Bronchoalveolar Lavage Fluid↗
PubMed1992

[Exogenous allergic alveolitis: assessment of antigen-specific IgG antibodies using a new chemiluminescence method].

The demonstration of elevated levels of antigen-specific IgG antibodies is of importance for the diagnostic workup of patients with a suspected hypersensitivity pneumonitis. We established a solid phase immunoassay for the determination of these antibodies based on chemiluminescence (CLIA). The CLIA demonstrated a low level of unspecific binding. The reproducibility of the CLIA was evaluated by calculating the intra- and inter-variation; the variation coefficient was 4% (intra-variation) resp. 13% (inter-variation). Using the CLIA we quantified IgG antibodies against Aspergillus fumigatus (A.f.), Micropolyspora faeni (M.f.) and Thermoactinomyces vulgaris (T. v.) in the sera of patients with farmer's lung (FL, n = 10), healthy farmers (n = 13) and normal volunteers without prior hay contact (n = 12). For all 3 antigens the antibody levels of patients with FL were significantly higher than the titers of the other groups. As a comparison all sera were tested with an established solid phase radioimmunoassay (RIA). Using the RIA a statistically significant difference could only be demonstrated between the antibody levels of patients with FL and of normal volunteers without prior hay contact and was limited to the antigens A.f. and M.f. Comparing the results achieved with both assays on a point by point basis there was a good correlation for the antigens A.f. (r = 0.69; p less than 0.0001) and M.f. (r = 0.74; p less than 0.0001), whereas the correlation for T.v. was not satisfying (r = 0.42, p less than 0.02). In summary the CLIA is a promising new method for the determination of antigen specific IgG antibodies with the advantages of a radioimmunoassay without its potential hazards.

Alveolitis, Extrinsic Allergic↗
PubMed1991

Isocyanate-induced asthma: results of inhalation tests with TDI, MDI and methacholine.

We performed diisocyanate inhalation tests (maximal concentration, 20 ppb; exposure time, 1-2 h) using toluene diisocyanate (TDI, n = 15) and diphenylmethane diisocyanate (MDI, n = 7) as well as methacholine challenges in 19 workers who had a clinical history of TDI/MDI-induced asthma. Additionally we tested volunteers who had no previous contact with diisocyanates: 10 healthy individuals with a negative methacholine test and 14 patients with asthma and a positive methacholine test were exposed to TDI. In all, 1 of the normal volunteers and 3 of the patients with asthma unrelated to diisocyanates showed a positive airway reaction to TDI, and 13 of the 19 diisocyanate workers displayed a positive result in the TDI/MDI inhalation test; however, only 6 of these 13 individuals reacted to methacholine. Furthermore, 3 of the 6 patients with a negative TDI/MDI challenge test demonstrated a significant response to methacholine. We conclude that bronchial hyperreactivity as evaluated by the methacholine challenge test is not closely related to isocyanate-induced bronchoconstriction and, therefore, the metacholine challenge is only of limited diagnostic value in patients with suspected isocyanate-induced asthma.

Asthma↗
PubMed1991

Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor.

Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease with a high capacity for inhibiting neutrophil elastase (NE), is produced by cells of mucosal surfaces including the human lung. The molar concentrations of SLPI in total respiratory tract epithelial lining fluid (ELF) were 56 +/- 10% that of alpha 1-antitrypsin, suggesting SLPI may be more important for the anti-NE protection of the pulmonary epithelial surface than previously thought. However, evaluation demonstrated that SLPI in respiratory ELF was only one-third functional. Studies aerosolizing recombinant SLPI (rSLPI) to sheep demonstrated that in the short term, neither aerosolization and alveolar deposition nor the lavage procedure inactivated the SLPI molecule. In vitro studies with rSLPI demonstrated that exposure to oxidants did not modify the form of the molecule, while exposure to oxidants and NE caused the molecule to be cleaved from 12 to 8 kD. Consistent with this, evaluation of SLPI in lavage fluid of individuals with cystic fibrosis (a condition with oxidants and NE on the respiratory epithelium) showed that the SLPI was degraded. However, evaluation of SLPI in normal ELF by molecular sieve analysis and Western analysis demonstrated an intact 12-kD molecule, suggesting that the partial inactivation of SLPI in normals in vivo is not because it is complexed to NE or exposed to oxidants + NE. Together, these observations demonstrate that SLPI is present in large amounts in respiratory ELF, but since the majority of the SLPI is inactive, it likely does not play a significant role in protecting the normal respiratory epithelium, except perhaps in the upper airways where the levels of SLPI are the highest.

Adult↗
PubMed1991

Risk factors for emphysema. Cigarette smoking is associated with a reduction in the association rate constant of lung alpha 1-antitrypsin for neutrophil elastase.

The increased risk of developing emphysema among individuals who smoke cigarettes and who have normal levels of alpha 1-antitrypsin (alpha 1AT) is hypothesized to result from a decrease in the antineutrophil elastase capacity of the lower respiratory tract alpha 1AT of smokers compared with nonsmokers. To evaluate this hypothesis we compared the time-dependent kinetics of the inhibition of neutrophil elastase by lung alpha 1AT from healthy, young cigarette smokers (n = 8) and nonsmokers (n = 12). alpha 1-antitrypsin was purified from lavage fluid using affinity and molecular sieve chromatography, and the association rate constant (k assoc) for neutrophil elastase quantified. The k assoc of smoker plasma alpha 1AT (9.5 +/- 0.5 X 10(6) M-1s-1) was similar to that of nonsmoker plasma (9.3 +/- 0.7 X 10(6) M-1s-1, P greater than 0.5). In marked contrast, the k assoc of smoker lower respiratory tract alpha 1AT was significantly lower than that of nonsmoker alpha 1AT (6.5 +/- 0.4 X 10(6) M-1s-1 vs. 8.1 +/- 0.5 X 10(6) M-1s-1, P less than 0.01). Furthermore, the smoker lower respiratory tract alpha 1AT k assoc was significantly less than that of autologous plasma (P less than 0.01). When considered in the context of the concentration of alpha 1AT in the lower respiratory tract epithelial lining fluid, the inhibition time for neutrophil elastase of smoker lung alpha 1AT was twofold greater than that of nonsmoker lung alpha 1AT (smoker: 0.34 +/- 0.05 s vs. nonsmoker: 0.17 +/- 0.05 s, P less than 0.01). Consequently, for concentrations of alpha 1AT in the lower respiratory tract it takes twice as long for an equivalent amount of neutrophil elastase to be inhibited in the smoker's lung compared with the nonsmoker's lung. These observations support the concept that cigarette smoking is associated with a decrease in the lower respiratory tract neutrophil elastase inhibitory capacity, thus increasing the vulnerability of the lung to elastolytic destruction and thereby increasing the risk for the development of emphysema.

Emphysema↗
PubMed1990

Augmentation of glutathione in the fluid lining the epithelium of the lower respiratory tract by directly administering glutathione aerosol.

Glutathione (GSH), a cysteine-containing tripeptide, functions as an antioxidant, provides cells with cysteine, and is required for optimal function of the immune system. Because the epithelial-lining fluid (ELF) of the lower respiratory tract normally contains high GSH levels and lung ELF GSH deficiency states can exist, we evaluated the feasibility of augmenting lung ELF GSH levels by (i) administering GSH to sheep i.v. and by direct aerosolization and then (ii) measuring the GSH levels in lung ELF, lung lymph, venous plasma, and urine. When GSH (600 mg) was administered i.v. (n = 11), GSH levels in venous plasma, lung lymph, and ELF rose, but only transiently, suggesting the i.v. route would not deliver adequate GSH to the alveolar epithelial surface. For directly administering GSH to the lung by the aerosol route, in vitro studies were first conducted to show that greater than 50% of a GSH solution could be converted to droplets less than 3 microns in aerodynamic diameter without oxidizing the GSH. To target functional GSH to the lower respiratory tract, an aerosolized solution of GSH (600 mg) was administered to sheep (n = 12). Significantly, the GSH level in ELF increased 7-fold at 30 min (preaerosol, 45.7 +/- 10 microM; 30-min postaerosol, 337 +/- 64 microM; P less than 0.001). The ELF GSH levels remained above baseline at 1 hr (P less than 0.01), returning toward baseline over a 2-hr period. In contrast, GSH levels in lung lymph, venous plasma, and urine were not significantly increased during the period--i.e., aerosol therapy selectively augmented the GSH levels only at the lung epithelial surface. Thus, functional GSH can be delivered by aerosol to directly augment the ELF GSH levels of the lower respiratory tract. Such an approach may prove useful in treating a variety of lung disorders.

Aerosols↗
PubMed1990

Molecular basis of alpha 1-antitrypsin deficiency and emphysema associated with the alpha 1-antitrypsin Mmineral springs allele.

The Mmineral springs alpha 1-antitrypsin (alpha 1AT) allele, causing alpha 1AT deficiency and emphysema, is unique among the alpha 1AT-deficiency alleles in that it was observed in a black family, whereas most mutations causing alpha 1AT deficiency are confined to Caucasian populations of European descent. Immobilized pH gradient analysis of serum demonstrated that alpha 1AT Mmineral springs migrated cathodal to the normal M2 allele. Evaluation of Mmineral springs alpha 1AT as an inhibitor of neutrophil elastase, its natural substrate, demonstrated markedly lower than normal function. Characterization of the alpha 1AT Mmineral springs gene demonstrated that it differed from the common normal M1(Ala213) allele by a single-base substitution causing the amino acid substitution Gly-67 (GGG)----Glu-67 (GAG). Capitalizing on the fact that this mutation creates a polymorphism for the restriction endonuclease AvaII, family analysis demonstrated that the Mmineral springs alpha 1AT allele was transmitted in an autosomal-codominant fashion. Evaluation of genomic DNA showed that the index case was homozygous for the alpha 1AT Mmineral springs allele. Cytoplasmic blot analysis of blood monocytes of the Mmineral springs homozygote demonstrated levels of alpha 1AT mRNA transcripts comparable to those in cells of a normal M1 (Val213) homozygote control. Evaluation of in vitro translation of Mmineral springs alpha 1AT mRNA transcripts demonstrated a normal capacity to direct the translation of alpha 1AT. Evaluation of secretion of alpha 1AT by the blood monocytes by pulse-chase labeling with [35S]methionine, however, demonstrated less secretion by the Mmineral springs cells than normal cells. To characterize the posttranslational events causing the alpha 1AT-secretory defect associated with the alpha 1AT Mmineral springs gene, retroviral gene transfer was used to establish polyclonal populations of murine fibroblasts containing either a normal human M1 alpha 1AT cDNA or an Mmineral springs alpha 1AT cDNA and expressing comparable levels of human alpha 1AT mRNA transcripts. Pulse-chase labeling of these cells with [35S]methionine demonstrated less secretion of human alpha 1AT from the Mmineral springs cells than from the M1 cells, and evaluation of cell lysates also demonstrated lower amounts of intracellular human alpha 1AT in the Mmineral springs cells than in the normal M1 control cells. Thus, the Gly-67 --> Glu mutation that characterizes Mmineral springs causes reduced alpha 1AT secretion on the basis of aberrant posttranslational alpha 1AT biosynthesis by a mechanism distinct from that associated with the alpha 1AT Z allele, whereby intracellular aggregation of the mutant protein is etiologic of the alpha 1AT-secretory defect. Furthermore, for the alpha 1AT protein that does reach the circulation, this mutation markedly affects the ability of the molecule to inhibit neutrophil elastase; i.e., the alpha 1AT Mmineral springs allele predisposes to emphysema on the basis of serum apha 1AT deficiency coupled with alpha AT dysfunction.

Alleles↗
PubMed1990

Aerosolization of recombinant SLPI to augment antineutrophil elastase protection of pulmonary epithelium.

In a variety of lung diseases the respiratory epithelial surface must contend with an increased burden of neutrophil elastase (NE). One candidate for augmenting epithelial anti-NE protection is the secretory leukoprotease inhibitor (SLPI). In vitro evaluation demonstrated that 96 +/- 1% of the recombinant SLPI (rSLPI) molecules were capable of inhibiting NE, with an association rate constant of 7.1 +/- 0.1 X 10(6) M-1.s-1. Evaluation of rSLPI after in vitro and in vivo aerosolization showed that aerosolization did not alter rSLPI. Aerosolization of a single dose of 50 mg rSLPI to sheep resulted in a fourfold increase of the anti-NE capacity in epithelial lining fluid (ELF) at 3 h, with a half-life in ELF of 12 h. After aerosolization some rSLPI appeared in lung lymph. Simultaneous aerosolization of rSLPI and recombinant alpha 1-antitrypsin (rAAT) demonstrated a molar ratio of the concentration in lymph to the concentration in ELF 3 h after the aerosol eightfold higher for rAAT than for rSLPI. Overall, these observations demonstrate that it is feasible to use aerosolized rSLPI to directly augment the anti-NE capacity of the lung, particularly on the pulmonary epithelial surface.

Aerosols↗
PubMed1989

Molecular basis of the liver and lung disease associated with the alpha 1-antitrypsin deficiency allele Mmalton.

Alpha 1-Antitrypsin (alpha 1AT) deficiency is characterized by reduced serum levels of alpha 1AT and a risk for the development of emphysema and liver disease. However, whereas there is an increased risk for emphysema associated with at least 10 alpha 1AT deficiency and null alleles, the hepatic disease is observed only in a subset of these alleles, suggesting that it is not the reduced serum levels of alpha 1AT per se which cause the liver disease. The present study characterizes the alpha 1AT deficiency allele Mmalton, an allele that like the common Z deficiency mutation (Glu342----Lys) is associated with both alpha 1AT deficiency and hepatic disease. Capitalizing on the identification of the homozygous inheritance of the rare Mmalton alpha 1AT deficiency allele, it was demonstrated that although caused by a very different mutation, the Mmalton allele shares with the Z allele the association of liver disease with the same type of abnormalities of alpha 1AT biosynthesis. Cloning of the Mmalton gene and sequence analysis demonstrated that it differs from the normal alpha 1AT M2 allele by deletion of the entire codon (TTC) for residue Phe52. Liver biopsy of the Mmalton homozygote revealed inflammation, mild fibrosis, and intrahepatocyte accumulation of alpha 1AT. Evaluation of de novo alpha 1AT biosynthesis in alpha 1AT-synthesizing cells of this individual demonstrated normal levels of alpha 1AT mRNA transcripts but abnormal intracellular accumulation of newly synthesized alpha 1AT at the level of the rough endoplasmic reticulum with consequent reduced alpha 1AT secretion. Finally, retroviral gene transfer of a normal alpha 1AT cDNA and an alpha 1AT cDNA with the Mmalton Phe52 deletion into murine cells demonstrated that the Mmalton cells reproduced the abnormal accumulation of newly synthesized alpha 1AT, thus directly demonstrating that the deletion mutation is responsible for the intracellular accumulation of the newly synthesized alpha 1AT. Thus, not only is the liver disease associated with alpha 1AT deficiency restricted to a subset of alpha 1AT deficiency alleles, it appears to be restricted to those alleles associated with intracellular accumulation of newly synthesized alpha 1AT, suggesting that it is the abnormal intrahepatocyte alpha 1AT accumulation which incites the liver injury.

Alleles↗