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)

Toxic oxygen free radicals are believed to play a role in the pathogenesis of a number of respiratory diseases. In particular, pulmonary emphysema may occur because of the oxidative impairment of alpha 1-proteinase inhibitor (alpha 1-PI). We report in vitro data on a new thiol agent, P 1507 [N-5-(thioxo-L-prolyl)-L-cysteine], obtained in a series of experiments designed in view of its therapeutic potential in these clinical conditions. We found that P 1507 at the concentration of 5 x 10(-6) M was able to almost fully abolish the PMA-triggered PMN-induced oxidative impairment of alpha 1-PI. Protection may be due to the radical scavenger ability of P 1507, that markedly reduced superoxide anion production from PMNs. We also found that P 1507 did not significantly impair other defence mechanisms of PMNs (i.e. phagocytosis, chemotaxis and bactericidal activity). The release of cytokines (TNF-alpha, IL-6 and IL-8) from monocytes was not altered in the presence of P 1507. We conclude that the compound P 1507 may be considered for treatment of clinical conditions characterized by overload of oxidants, on the basis of its ability in preventing the oxidative damage of alpha 1-PI and of a lack of unwanted inhibitory effects towards defence mechanisms of phagocytes.
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PMID:Interactions of P 1507, a new antioxidant agent, with phagocyte functions. 774 Oct 36

Interleukin-8 (IL-8) belongs to the family of chemotactic cytokines and has been shown to activate neutrophils in vitro and in vivo. In this study, we measured IL-8 concentration in the serum of patients with pulmonary emphysema or bronchial asthma. IL-8 concentration in serum of emphysema patients was significantly higher than in asthmatics; in emphysema patients it was significantly correlated with the smoking index and the annual decrease of FEV1.0. In asthmatics IL-8 concentration was below the level of detection, but was markedly increased during exacerbation of asthma. Our findings suggest that IL-8 may be one of the causal factors in these diseases.
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PMID:Clinical significance of serum concentration of interleukin 8 in patients with bronchial asthma or chronic pulmonary emphysema. 881 71

Neutrophils isolated from patients with chronic bronchitis and emphysema have been shown to have enhanced responses to formyl peptides when assessed in vitro compared to age, sex matched controls. It is currently unclear whether the observed differences are due to a 'priming' effect by a second agent in vivo, or whether this is a primary difference in the neutrophils. We have studied the effects of interleukin-8, which is thought to be one of the major pro-inflammatory cytokines in chronic lung disease and granulocyte macrophage colony stimulating factor (GMCSF), in order to assess their effects on neutrophil chemotaxis and connective tissue degradation. In addition, we have assessed the effect of preincubation of these agents with neutrophils for 30 min followed by stimulation with F-Met-Leu-Phe (FMLP) to investigate any possible 'priming' effect that may be relevant to our clinical data. We report suppression of neutrophil chemotaxis to FMLP following incubation of the neutrophils with both IL-8 and GMCSF. However, we have observed an additive effect of IL-8 and FMLP for neutrophil degranulation leading to fibronectin degradation. The results suggest that IL-8 does not 'prime' neutrophils for subsequent FMLP stimulation as observed in vivo. Although the results for GMCSF were similar for the chemotactic response, the agent also had a synergistic effect on connective tissue degradation. However, it is concluded that neither agent could explain the enhanced neutrophil responses seen in our patients.
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PMID:The effect of interleukin-8 and granulocyte macrophage colony stimulating factor on the response of neutrophils to formyl methionyl leucyl phenylalanine. 968 20

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

In bronchial asthma, eosinophils and neutrophils are activated, so that the production of active oxygen species increases, causing airway epithelial injury. Suplatast tosilate (IPD Capsules) is a novel immunomodulating antiallergic drug that acts against bronchial asthma through a new mechanism. To evaluate the effects of suplatast tosilate on mononuclear cell-mediated IL-8 production, and neutrophil-mediated active oxygen species production at sites of inflammation, we collected peripheral blood from healthy subjects and separated the neutrophils as well as mononuclear cells. Suplatast tosilate was added at a concentration of 1 x 10(-6), 1 x 10(-7) or 1 x 10(-8) M, and cells were incubated for 10 min at 37 degrees C. Then, the neutrophils were stimulated with fMLP, and luminol-dependent chemiluminescence (LDCL) was measured, while IL-8 production was determined with an ELISA kit. Suplatast tosilate (1 x 10(-6) M) inhibited neutrophil-mediated active oxygen species production by 12.4% in terms of the peak, and by 16% in terms of the integral value. Moreover, it significantly inhibited mononuclear cell-mediated IL-8 production at concentrations of 1 x 10(-6), 1 x 10(-7) and 1 x 10(-8) M, in a concentration-dependent manner. This study indicated that suplatast tosilate may inhibit neutrophil infiltration by suppressing monocyte-mediated IL-8 production, and it may also inhibit the activation of neutrophils at sites of inflammation. These results suggest the possibility that suplatast tosilate may not only be of benefit for asthma, but may also prevent or control pulmonary fibrosis or emphysema, for which no effective treatment is presently available.
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PMID:Effects of suplatast tosilate (IPD Capsules) on the production of active oxygen by neutrophils and of IL-8 by mononuclear cells. 1140 12

Exposure to airborne endotoxin in infancy may protect against asthma by promoting enhanced T(H)1 response and tolerance to allergens. On the other hand, later in life, it adversely affects patients with asthma. Endotoxin binding to receptors on macrophages and other cells generates IL-12, which inhibits IgE responses. It also generates cytokines like IL-1, TNF-alpha, and IL-8, which cause inflammation. These signal transduction pathways resemble those leading to the generation of cytokines, such as IL-4, IL-13, and IL-5, which are responsible for the inflammation of IgE-mediated allergic disease. The main difference seems to be that endotoxin recruits neutrophils, but IgE recruits eosinophils, and the details of the tissue injury from these granulocytes differ. Sources of airborne endotoxin include many agricultural dusts, aerosols from contaminated water in many industrial plants, contaminated heating and air-conditioning systems, mist-generating humidifiers, and damp or water-damaged homes. Acute inhalation of high concentrations of endotoxin can cause fever, cough, and dyspnea. Chronic inhalation of lesser amounts causes chronic bronchitis and emphysema and is associated with airway hyperresponsiveness. Airborne endotoxin adversely affects patients with asthma in 3 ways: (1) by increasing the severity of the airway inflammation; (2) by increasing the susceptibility to rhinovirus-induced colds; and (3) by causing chronic bronchitis and emphysema with development of irreversible airway obstruction after chronic exposure of adults. The most effective management is mitigating exposure. The potential of drug treatments requires further clinical investigation.
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PMID:Endotoxin-stimulated innate immunity: A contributing factor for asthma. 1149 29

Acute viral respiratory tract infections are well known to precipitate asthma attacks and acute exacerbations of chronic obstructive pulmonary disease, but their role in the pathogenesis of chronic disease is poorly defined. Double-stranded DNA viruses have the ability to persist in airway epithelial cells long after the acute infection has cleared. During these latent infections, viral genes are expressed at the protein level without replication of a complete virus. The expression of the adenoviral trans-activating protein has been demonstrated in the airway epithelium of both human and animal lungs and is associated with an amplification of the cigarette smoke-induced inflammatory response. Studies of cultured human airway epithelial cells have also shown that transfection with this viral gene upregulates the expression of intercellular adhesion molecule 1 and interleukin 8 by these cells when they are challenged with endotoxin. In guinea pigs, cigarette smoke-induced emphysema is amplified by latent adenoviral infection. Furthermore, this infection independently increased the number of CD-8 cells, whereas the cigarette smoke independently increased the number of CD-4 cells in the inflammatory infiltrate. On the other hand, allergen-induced lung inflammation was uninfluenced by latent adenoviral infection in the guinea pig, but the latent infection caused the eosinophilic component of this response to become steroid resistant. These studies suggest that latent adenoviral infections may have a role in the pathogenesis of obstructive airway disease by amplifying the response to cigarette smoke and inducing steroid resistance.
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PMID:Role of latent viral infections in chronic obstructive pulmonary disease and asthma. 1173 71

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

An early response to cigarette smoke is an influx of leukocytes into the lung. Alveolar epithelial type II (ATII) cells may contribute by releasing chemokines in response to cigarette smoke and neutrophil elastase (NE). Human ATII cells were purified from normal regions of lungs resected for carcinoma (n = 14). In vitro, these cells exhibited ATII cell characteristics: lamellar bodies, apical microvilli, tight junctions, and expressed surfactant apoprotein C. Basal ATII cell release of five chemokines ranked as follows: monocyte chemotactic protein (MCP)-1 > interleukin (IL)-8 > growth-related oncogene (GRO)-alpha > macrophage inflammatory protein (MIP)-1alpha > regulated on activation, normal T cell expressed and secreted (RANTES). MIP-1alpha and RANTES were often not detectable. After stimulation with a mixture of lipopolysaccharide/endotoxin (LPS), tumor necrosis factor-alpha, IL-1beta, and IFN-gamma, MCP-1 and IL-8 secretion rose 4-6-fold, whereas GRO-alpha rose 25-fold. NE stimulated IL-8 mRNA expression, and 10nM NE stimulated IL-8 secretion; however, 100 nM NE caused a decrease in extracellular IL-8, MCP-1, and GRO-alpha, attributed to proteolysis. Cigarette smoke extract (CSE) inhibited IL-8 mRNA expression and release of all chemokines. Glutathione protected against the effects of CSE, suggesting oxidative mechanisms. GRO-alpha, important in growth and repair, was sensitive to both stimulation, by LPS:cytokines, and inhibition, by CSE. Thus, contrary to the original hypothesis, high concentrations of NE and CSE resulted in reduced extracellular chemokine levels. We hypothesize that reduced ATII cell-derived chemokine levels compromise alveolar repair, contributing to cigarette smoke-induced alveolar damage and emphysema.
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PMID:Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase. 1503 39

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


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