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)

Glycosaminoglycans are constituents of proteoglycans, which are integral components of lung connective tissue. Glycosaminoglycans not only provide structural support to organs, but also influence extracellular matrix assembly, cell adhesion, and cell proliferation. Changes in the metabolism of glycosaminoglycans have been noted in several pulmonary diseases, for example, pulmonary fibrosis and emphysema. We studied quantitative and qualitative changes of glycosaminoglycans in the lungs of rats exposed to a range of ozone levels (0, 0.12, 0.5, 1.0 parts per million) for 20 months. Glycosaminoglycans were isolated from dry-defatted lung tissues through successive digestions by pronase, papain, and 2 M sodium hydroxide. The glycosaminoglycans then were fractionated into individual components using high-performance liquid chromatography. The concentration of total glycosaminoglycans in the tissues varied from 1.5 to 4.2 micrograms of uronate/mg of dry-defatted tissue. Although wide variations in total glycosaminoglycan concentrations exist among individual animals within each exposure group, regression analyses of data indicate a monotonic and statistically significant decrease of total glycosaminoglycans after ozone exposure (p = 0.02). Among individual glycosaminoglycans, hyaluronan, chondroitin 4-sulfate, and chondroitin 6-sulfate levels decreased significantly (p < 0.001, p < 0.05, and p < 0.01, respectively) in animals exposed to ozone when compared with control animals. Heparan sulfate concentration exhibited a significant (p < 0.05) trend toward increase with increasing doses of ozone, but the difference in heparan sulfate concentration between ozone-exposed animals and control animals was not significant. Gel filtration studies of glycosaminoglycans in pooled samples indicated that the molecular size of hyaluronan in animals exposed to ozone was lower than it was in control animals. We noted differences in heparan sulfate's chemical properties and affinity to antithrombin III in ozone-exposed animals and control animals. Although these studies do not provide the mechanism responsible for the observed changes in the lung glycosaminoglycans in ozone-exposed animals, the observations indicate that inhalation of ozone for 20 months affects normal cellular metabolism of proteoglycans, which may contribute to the functional impairment of the lung.
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PMID:Consequences of prolonged inhalation of ozone on F344/N rats: collaborative studies. Part III: Effects on complex carbohydrates of lung connective tissue. 781 21

In patients with emphysema the integrity of the extracellular matrix (connective tissue skeleton) is compromised. In this study we analyzed glycosaminoglycans, which are main constituents of this matrix, in urines from patients with chronic obstructive pulmonary disease (COPD)/emphysema. Glycosaminoglycans (GAGs) were purified by anion exchange chromatography and quantified using the 1,9-dimethylmethylene blue assay. Heparan sulfate (HS) was assayed using three different chemical methods: digestion with heparitinase or with nitrous acid and by use of an adapted 1,9-dimethylmethylene blue assay. A specific epitope on the HS molecule, defined by the monoclonal antibody JM403, was determined using an inhibition enzyme immunoassay. In patients with COPD total urinary glycosaminoglycan and HS content were not altered. The JM403 epitope of HS, however, was greatly decreased in patients (0.6 versus 4.1 units/mg creatinine for control subjects, p < 0.0001). A similar pattern was observed when patients with bronchial carcinoma with and without emphysema were compared (0.4 versus 2.4 units/mg creatinine respectively, p < 0.0005). Patients with sarcoidosis did not show a decreased epitope content. These results indicate a structural change or an altered processing of the HS molecule in patients with emphysema. Taking into consideration the importance of HS for the stability of the alveolar extracellular matrix, this change may be associated with the pathogenesis of emphysema.
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PMID:Altered composition of urinary heparan sulfate in patients with COPD. 888 91

The possible involvement of proteoglycans in the pathogenesis of emphysema was studied in rats by a single intratracheal instillation of p-nitrophenyl-beta-D-xylopyranoside (beta-D-xyloside), an inhibitor of proteoglycan synthesis. The first 3 days after instillation are characterized by mild hemorrhages, some infiltration of inflammatory cells, and edema. After 1 wk, lung morphology is normal again. Forty days after instillation, considerable parenchymal destruction has occurred as determined by the mean linear intercept (81 +/- 12 microns versus 57 +/- 5 microns for control [P < 0.001]). Pulmonary fibrosis is not observed. Instillation with p-nitrophenyl-alpha-D-xylopyranoside and p-nitrophenol do not induce parenchymal destruction, indicating the specificity of beta-D-xyloside action. Urinary glycosaminoglycan (GAG) content of the beta-D-xyloside-treated rats is increased 15-fold during the first day after instillation, mainly due to elevated levels of chondroitin sulfate and dermatan sulfate. The increase is correlated to the extent of parenchymal destruction after 40 days (r = 0.68; P < 0.002). At day 2 and thereafter, levels are normal again. A short-term increase in dermatan and chondroitin sulfate content is also observed in serum, bronchoalveolar lavage (BAL) fluid, and lung tissue. Heparan sulfate content is decreased in BAL fluid and lung tissue. Instillation with p-nitrophenyl-alpha-D-xylopyranoside and p-nitrophenol do not induce elevated GAG concentration in urine. We suggest that a disturbance in proteoglycan synthesis accompanied by an increase of (beta-D-xyloside-primed) free GAGs results in loss of stability and integrity of the alveolar wall, leading to parenchymal destruction and emphysematous lesions. beta-D-xyloside treatment may be an alternative experimental method for inducing emphysema.
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PMID:Induction of emphysematous lesions in rat lung by beta-D-xyloside, an inhibitor of proteoglycan synthesis. 899 82

To characterize the changes in the extracellular matrix in smoking-related pulmonary emphysema, we undertook immunohistochemical studies in lung tissues from controls (n = 7), from patients with mild (n = 11) and severe (n = 8) emphysema, and from patients with lung fibrosis (n = 6). We studied collagens, laminin, fibronectin, proteoglycans (PGs), and beta1-integrins. The majority of the patients with severe emphysema showed diminished staining for the interstitial PGs, decorin and biglycan, in the peribronchiolar area, compared with patients in the control and fibrosis groups. Only a minority of patients with mild emphysema showed this diminished staining. In contrast, decorin and biglycan were well preserved in the perivascular area of all of the specimens from the emphysema group. Heparan sulfate PG staining was diminished in the respiratory airspace walls of patients with emphysema and fibrosis. Staining for Types I, III, and IV collagen, as well as for laminin, fibronectin, and the integrins, showed no differences between the four groups. The specific loss of interstitial PGs may be crucial for elastic recoil loss and subsequent bronchiolar obstruction, as seen in patients with smoking-related emphysema.
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PMID:Proteoglycan changes in the extracellular matrix of lung tissue from patients with pulmonary emphysema. 1043 Feb 74

Heparan sulfate chains are initially synthesized on core proteins as linear polysaccharides composed of glucuronic acid-N-acetylglucosamine repeating units and subjected to marked structural modification by sulfation at various places and epimerization of hexuronic acid residues (C5-epimerase) at the Golgi lumen and further by 6-O-desulfation at the cell surface, which generates their characteristic divergent fine structures. This chapter focuses on the biological and physiological functions of 6-O-sulfation in HS and the characterization of the enzymes catalyzing 6-O-sulfation (HS6ST). HS6STs in mammals such as humans and mice comprise of three isoforms (HS6ST-1, -2, and -3) and one alternatively spliced form of HS6ST-2 (HS6ST-2S). Each of these isoforms has distinct substrate preferences, albeit overlapping each other. These HS6ST isoforms are expressed in a spatiotemporally regulated manner in most organs. HS6ST-1-deficient mice are lethal mostly at later embryonic stages and exhibit abnormal angiogenesis in labyrinthine zone of placenta and aberrant lung morphology similar to pulmonary emphysema. These knockout mice also exhibit retinal axon guidance abnormality at the optic chiasm. Other HS6ST-deficient animals reveal various malformations in muscle development and branching morphology of the caudal vein of zebrafish, in tracheal formation of Drosophila, and in axon guidance of ventral nerve cord interneurons of Caenorhabditis elegans. Mouse embryonic fibroblasts prepared from HS6ST-1/HS6ST-2 double knockout mice did produce HS lacking 6-O-sulfation and responded differently to various FGFs dependent signaling.
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PMID:Mice deficient in heparan sulfate 6-O-sulfotransferase-1. 2080 42