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)

Elastase/anti-elastase imbalance is a hallmark of emphysema, a chronic obstructive pulmonary disease associated with the rupture and inefficient repair of interstitial elastin. We report that neutrophil elastase (NE) at low physiologic concentrations, ranging from 35 nm to 1 microm, invokes transient, peaking at 15 min, activation of extracellular signal-regulated kinases 1 and 2 (ERK) in elastogenic lung fibroblasts. ERK activation is preceded by the release of soluble 25-26-kDa forms of epidermal growth factor (EGF) and transactivation of EGF receptor (EGFR) in NE-exposed cells. The stimulatory effect of NE on ERK is abrogated in the presence of anti-EGF-neutralizing antibodies, EGFR tyrosine kinase inhibitor (AG1478), and ERK kinase inhibitor (PD98059), as well as abolished in both EGFR-desensitized and endocytosis-arrested fibroblasts. Nuclear accumulation of activated ERK is associated with transient, peaking at 30 min, induction of c-Fos and sustained, observed at 24-48 h, decrease of tropoelastin mRNA levels in NE-challenged cells. Pretreatment of fibroblasts with AG1478 or PD98059 abrogates the NE-initiated tropoelastin mRNA suppression. We conclude that proteolytically released EGF signals directly via EGFR and ERK to down-regulate tropoelastin mRNA in NE-challenged lung fibroblasts.
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PMID:Elastase-released epidermal growth factor recruits epidermal growth factor receptor and extracellular signal-regulated kinases to down-regulate tropoelastin mRNA in lung fibroblasts. 1188 28

Hereditary cutis laxa comprises a heterogeneous group of connective tissue disorders characterized by loose skin and variable systemic involvement. Autosomal dominant and recessive as well as X-linked forms have been described. Some dominant forms are caused by mutations in the elastine gene (ELN). The X-linked form is now classified in the group of copper transport diseases. The genetic defect underlying the autosomal recessive (AR) forms of cutis laxa is not known. The phenotypic abnormalities recently observed in a fibulin-5 knockout mouse model are reminiscent of human AR cutis laxa type I. Both share cutis laxa, lung emphysema and arterial involvement. Molecular study of the fibulin-5 (FBLN5) gene in a large consanguineous Turkish family with four patients affected by AR cutis laxa type I demonstrated the presence of a homozygous missense mutation (T998C) in the FBLN5 gene resulting in a serine-to-proline (S227P) substitution in the fourth calcium-binding epidermal growth factor-like domain of fibulin-5 protein. This amino acid substitution is predicted to have important structural and functional consequences for normal elastogenesis. As such, we provide evidence that a genetic defect in fibulin-5 (FBLN5, also known as EVEC or DANCE) is responsible for a recessive form of cutis laxa in humans.
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PMID:Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. 1218 63

Chronic obstructive pulmonary disease (COPD) is characterized by chronic obstruction of expiratory flow affecting peripheral airways, associated with chronic bronchitis (mucus hypersecretion with goblet cell and submucosal gland hyperplasia) and emphysema (destruction of airway parenchyma), together with fibrosis and tissue damage, and inflammation of the small airways. Cytokines are extracellular signalling proteins. Increased levels of interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and IL-8 have been measured in sputum, with further increases during exacerbations, and the bronchiolar epithelium over-expresses monocyte chemotactic protein (MCP)-1 and IL-8. IL-8 can account for some chemotactic activity of sputum, and sputum IL-8 levels correlate with airway bacterial load and blood myeloperoxidase levels. The expression of chemokines such as regulated on activation, normal T-cell expressed and secreted (RANTES) may underlie the airway eosinophilia observed in some COPD patients. Cytokines may be involved in tissue remodelling. TNF-alpha and IL-1beta stimulate macrophages to produced matrix metalloproteinase-9 (MMP-9), and bronchial epithelial cells to produce extracellular matrix glycoproteins such as tenascin. Increased expression of transforming growth factor-beta (TGFbeta) and of epidermal growth factor (EGF) occurs in the epithelium and submucosal cells of patients with chronic bronchitis. TGFbeta and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression. The cytokine profile seen in chronic obstructive pulmonary disease is different from that observed in asthma. The role of these cytokines needs to be defined and there is a potential for anticytokine therapy in chronic obstructive pulmonary disease.
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PMID:Cytokines in chronic obstructive pulmonary disease. 1239 35

Alpha1,6-fucosyltransferase (Fut8) plays important roles in physiological and pathological conditions. Fut8-deficient (Fut8-/-) mice exhibit growth retardation, earlier postnatal death, and emphysema-like phenotype. To investigate the underlying molecular mechanism by which growth retardation occurs, we examined the mRNA expression levels of Fut8-/- embryos (18.5 days postcoitum [dpc]) using a cDNA microarray. The DNA microarray and real-time polymerase chain reaction (PCR) analysis showed that a group of genes, including trypsinogens 4, 7, 8, 11, 16, and 20, were down-regulated in Fut8-/- embryos. Consistently, the expression of trypsinogen proteins was found to be lower in Fut8-/- mice in the duodenum, small intestine, and pancreas. Trypsin, an active form of trypsinogen, regulates cell growth through a G-protein-coupled receptor, the proteinase-activated receptor 2 (PAR-2). In a cell culture system, a Fut8 knockdown mouse pancreatic acinar cell carcinoma, TGP49-Fut8-KDs, showed decreased growth rate, similar to that seen in Fut8-/- mice, and the decreased growth rate was rescued by the application of the PAR-2-activating peptide (SLIGRL-NH2). Moreover, epidermal growth factor (EGF)-induced receptor phosphorylation was attenuated in TGP49-Fut8-KDs, which was highly associated with a reduction of trypsinogens mRNA levels. The addition of exogenous EGF recovered c-fos, c-jun, and trypsinogen mRNA expression in TGP49-Fut8-KDs. Again, the EGF-induced up-regulation of c-fos and c-jun mRNA expression was significantly blocked by the protein kinase C (PKC) inhibitor. Our findings clearly demonstrate a relationship between Fut8 and the regulation of EGF receptor (EGFR)-trypsin-PAR-2 pathway in controlling cell growth and that the EGFR-trypsin-PAR-2 pathway is suppressed in TGP49-Fut8-KDs as well as in Fut8-/- mice.
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PMID:Down-regulation of trypsinogen expression is associated with growth retardation in alpha1,6-fucosyltransferase-deficient mice: attenuation of proteinase-activated receptor 2 activity. 1686 3

Mammalian alpha1,6-fucosyltransferase (FUT8) catalyses the transfer of a fucose residue from a donor substrate, guanosine 5'-diphosphate-beta-L-fucose to the reducing terminal N-acetylglucosamine (GlcNAc) of the core structure of an asparagine-linked oligosaccharide. Alpha1,6-fucosylation, also referred to as core fucosylation, plays an essential role in various pathophysiological events. Our group reported that FUT8 null mice showed severe growth retardation and emphysema-like lung-destruction as a result of the dysfunction of epidermal growth factor and transforming growth factor-beta receptors. To elucidate the molecular basis of FUT8 with respect to pathophysiology, the crystal structure of human FUT8 was determined at 2.6 A resolution. The overall structure of FUT8 was found to consist of three domains: an N-terminal coiled-coil domain, a catalytic domain, and a C-terminal SH3 domain. The catalytic region appears to be similar to GT-B glycosyltransferases rather than GT-A. The C-terminal part of the catalytic domain of FUT8 includes a Rossmann fold with three regions that are conserved in alpha1,6-, alpha1,2-, and protein O-fucosyltransferases. The SH3 domain of FUT8 is similar to other SH3 domain-containing proteins, although the significance of this domain remains to be elucidated. The present findings of FUT8 suggest that the conserved residues in the three conserved regions participate in the Rossmann fold and act as the donor binding site, or in catalysis, thus playing key roles in the fucose-transferring reaction.
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PMID:Crystal structure of mammalian alpha1,6-fucosyltransferase, FUT8. 1717 60

Chronic obstructive pulmonary disease (COPD) is characterised by chronic obstruction of expiratory flow affecting peripheral airways, associated with chronic bronchitis (mucus hypersecretion with goblet cell and submucosal gland hyperplasia) and emphysema (destruction of airway parenchyma), together with fibrosis and tissue damage, and inflammation of the small airways. Inflammatory mediators include lipid mediators, chemokines, cytokines, growth factors, reactive oxygen species and proteinases. Increased levels of interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and IL-8 have been measured in sputum, with further increases during exacerbations, and the bronchiolar epithelium over-expresses MCP-1 and IL-8. IL-8 and LTB4 can account for neutrophil chemotactic activity of sputum. The expression of chemokines such as RANTES and eotaxin may underlie the airway eosinophilia observed in some COPD patients. Reactive oxygen species can increase gene expression of many inflammatory mediators, such as IL-1 and TNFalpha from macrophages, alveolar and bronchial epithelial cells. TNFalpha and IL-1beta stimulate macrophages to produced matrix metalloproteinase-9 (MMP-9), and bronchial epithelial cells to produce extracellular matrix glycoproteins such as tenascin. Increased expression of transforming growth factor-beta (TGFbeta) and of epidermal growth factor (EGF) occurs in the epithelium and submucosal cells of patients with chronic bronchitis. TGFbeta and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression.
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PMID:Inflammatory mediators in chronic obstructive pulmonary disease. 1730 18

Homozygous mutant klotho (KL(-/-)) mice exhibit various characteristics resembling those of human aging, including emphysema. However, age-related changes of lungs have not been fully elucidated. Here, we investigated the structural, functional, biochemical, and cell kinetic alterations of lungs in KL(-/-) mice at 2-12 weeks of age. Homogeneous airspace enlargement and decreased lung elastic recoil were observed in KL(-/-) mice with aging. The apoptotic cells in airway walls in KL(-/-) mice were approximately 6 times greater than those in wild-type (KL(+/+)) mice at 2 weeks of age. However, lipid peroxidation and elastase activity of lungs were not increased in KL(-/-) mice. Western blotting suggested that protein levels of epidermal growth factor (EGF) and phosphorylated extracellular signal-regulated kinase were decreased in KL(-/-) mice. These data suggest that significantly increased apoptosis of airway cells via inhibition of the EGF-dependent pathway may be involved in the development of the aging lungs in KL(-/-) mice.
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PMID:Airspace enlargement with airway cell apoptosis in klotho mice: a model of aging lung. 1912 41

Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury.
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PMID:Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. 2084 4

Coal dust is a pollutant found in coal mines that are capable of inducing oxidative stress and inflammation, but the effects on lung metaplasia as an early step of carcinogenesis remain unknown. The purpose of the present study was to evaluate the effects of PM10 coal dust on lung histology, MUC5AC expression, epidermal growth factor (EGF) expression, and epidermal growth factor receptor (EGFR) expression. An experimental study was done on male Wistar rats, which were divided into the following groups: control groups exposed to coal dust for 14 days (at doses of 6.25 mg/m(3), 12.5 mg/m(3), and 25 mg/m(3)), and the groups exposed to coal dust for 28 days (at doses of 6.25 mg/m(3), 12.5 mg/m(3), and 25 mg/m(3)). EGF expressions in rat lungs were measured by ELISA. EGFR and MUC5AC were measured by a confocal laser scanning microscope. The bronchoalveolar epithelial image of the group exposed to coal dust for 14 and 28 days showed a epithelial rearrangement, hyperplastic (metaplastic) goblet cells, and scattered massive inflammatory cells. The pulmonary parenchymal image of the group of exposed to coal dust for 14 and 28 days showed scattered inflammatory cells filling up the pulmonary alveolar networks, leading to an appearance of thickened parenchymal alveoli until emphysema-like structure. There was no significant difference in MUC5AC, EGF, and EGFR expressions for 14-d exposure (p>0.05). There was no significant difference in EGF and EGFR expressions for 28-d exposure (p>0.05), but there was a significant difference in MUC5AC expression (p<0.05). We concluded that subchronic inhalation of coal dust particulate matter 10 induces bronchoalveolar reactive hyperplasia and rearrangement of epithelial cells which accompanied by decrease expression MUC5AC in male rats.
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PMID:Subchronic inhalation of coal dust particulate matter 10 induces bronchoalveolar hyperplasia and decreases MUC5AC expression in male Wistar rats. 2497 55

Neonatal Marfan syndrome (nMFS) is considered to be on the most severe end of the spectrum of type I fibrillinopathies. The common features of nMFS include ascending aortic dilatation, severe mitral and/or tricuspid valve insufficiency, ectopia lentis, arachnodactyly, joint contractures, crumpled ear, loose skin, and pulmonary emphysema.We describe a newborn male diagnosed with nMFS. He presented several atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Molecular analysis revealed a missense mutation at nucleotide 3217 (c.3217G>A) in exon 26 of the fibrillin-1 (FBN1) gene, resulting in the substitution of a glutamate for a lysine at codon 1073 (E1073K) in the 12th calcium binding epidermal growth factor-like domain of the FBN1 protein. Here we report a rare case of Nmfs with several combined atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Our report is the first atypical nMFS case with p.Glu1073Lys mutation of FBN1 in Korea and may help clinicians with the diagnosis and follow-up of atypical nMFS.
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PMID:Atypical Neonatal Marfan Syndrome with p.Glu1073Lys Mutation of FBN1: the First Case in Korea. 2791 24


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