Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Amino-substituted xanthene, thioxanthene and carbazole sulfonamido-carboxylic acid of carboxamido carboxylic acid derivatives, their use to treat metalloprotease mediated conditions, and especially to inhibit MMP-12, and to treat osteoarthritis, rheumatoid arthritis, atherosclerosis, heart failure, fibrosis, pulmonary emphysema, tumour growth, asthma and chronic obstructive pulmonary disorder (COPD). Compounds of this category are suggested to be particularly useful in the treatment of COPD.
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PMID:Selective MMP-12 inhibitors: WO-2008057254. 1945 79

Overexpression of macrophage elastase (MMP-12), a member of the matrix metalloproteinases family, can be linked to tissue remodeling and degradation in some inflammatory processes, such as chronic obstructive pulmonary disease (COPD), emphysema, rheumatoid arthritis (RA), and atherosclerosis. On this basis, MMP-12 can be considered an attractive target for studying selective inhibitors that are useful in the development of new therapies for COPD and other inflammatory diseases. We report herein the design, synthesis, and in vitro evaluation of a new series of compounds, possessing an arylsulfonyl scaffold, for their potential as selective inhibitors of MMP-12. The best compound in the series showed an IC50 value of 0.2 nM, with good selectivity over MMP-1 and MMP-14. A docking study was carried out on this compound in order to investigate its binding interactions with MMP-12, and NMR studies on the complex with the MMP-12 catalytic domain were able to validate the proposed binding mode.
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PMID:Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors. 1977 99

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible, though a number of pulmonary phenotypes are recognized. These include small airways diseases, chronic bronchitis and bronchiectasis, as well as pulmonary emphysema, which can be further subdivided by the zone of the lung which it affects, and its radiological appearance. In addition COPD is associated with a number of comorbidities, which are found more frequently than would be expected by chance, even after controlling for common etiological factors (such as smoking or steroid use). These comorbid conditions may be responsible for some of the deterioration and de-conditioning seen in COPD, as well as a significant proportion of mortality, and should be sought and managed where clinically appropriate. This review examines the prevalence and clinical features of associated comorbid conditions, including atherosclerosis, cardiac failure, diabetes, osteoporosis, cachexia, gastro-esophageal reflux disease and depression. A brief consideration of their management in COPD is also given. In addition evidence for the concept of pulmonary overspill leading to systemic inflammation, the consequences of systemic inflammation, the possibility of accelerated aging, and of how these concepts could relate to shared genetic risk factors for both comorbidity and pulmonary aspects of COPD is discussed.
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PMID:Chronic obstructive pulmonary disease and comorbidity: a review and consideration of pathophysiology. 2019 37

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor that plays a central role in cellular defense against oxidative and electrophilic insults by timely induction of antioxidative and phase-2 detoxifying enzymes and related stress-response proteins. The 5'-flanking regions of genes encoding these cytoprotective proteins contain a specific consensus sequence termed antioxidant response element (ARE) to which Nrf2 binds. Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries. During the early-phase of inflammation-mediated tissue damage, activation of Nrf2-ARE might inhibit the production or expression of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide synthase. It is likely that the cytoprotective function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the induction of pro-inflammatory genes. This review highlights the protective role of Nrf2 in inflammation-mediated disorders with special focus on the inflammatory signaling modulated by this redox-regulated transcription factor.
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PMID:A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. 1979 17

Mechanical stress to alveolar walls may cause progressive damage after an early-life insult such as exposure to environmental tobacco smoke (ETS). This hypothesis was examined by using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort aged 45-84 years, free of clinical cardiovascular disease, recruited from 6 US sites in 2000-2002. The MESA-Lung Study assessed a fractal, structural measure of early emphysema ("alpha," lower values indicate more emphysema) and a standard quantitative measure ("percent emphysema") from cardiac computed tomography scans. Childhood ETS exposure was assessed retrospectively as a report of living with one or more regular indoor smokers. Analyses included 1,781 nonsmokers (<100 cigarettes, 20 cigars, or 20 pipefulls in their lifetime and urinary cotinine levels <100 ng/mL); mean age was 61 years (standard deviation, 10), and 65% were women. Childhood ETS exposure from 2 or more smokers (17%) compared with none (52%) was associated with 0.05 lower alpha and 2.8 higher percent emphysema (P for trend = 0.04 and 0.01, respectively) after adjustment for demographic, anthropometric, parental, and participant characteristics, as well as adult exposures (e.g., cumulative residential air pollution exposure, exposure to ETS as an adult). Childhood ETS exposure was associated with detectable differences on computed tomography scans of adult lungs of nonsmokers.
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PMID:Association of environmental tobacco smoke exposure in childhood with early emphysema in adulthood among nonsmokers: the MESA-lung study. 1994 75

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Patients with COPD are at increased risk of cardiovascular diseases, osteoporosis and lung cancer. Although some of the associations between COPD and atherosclerosis may be the result of common risk factors such as smoking, epidemiological evidence suggest that impaired lung function is a risk factor for increased cardiovascular death, independent of tobacco use. This phenomenon may be related to common genetic predisposition for atherosclerosis and emphysema. Chronic obstructive pulmonary disease, like atherosclerosis, is a disease of systemic inflammation and may hasten the progression of atherosclerosis and contribute to the higher rate of death in COPD. This article reviews close relationship between COPD and cardiovascular diseases, mainly atherosclerosis. The authors also present some preliminary data suggesting a possible influence of statin therapy on the clinical course of COPD.
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PMID:[Chronic obstructive pulmonary disease and cardiovascular diseases]. 2016 16

Tobacco smoking has been considered the most important risk factor for chronic obstructive pulmonary disease (COPD) development. However, not all smokers develop COPD and other environmental and genetic susceptibility factors underlie disease pathogenesis. Recent studies have indicated that the impairment of TLR signaling might play a crucial role in the development of emphysema. For this purpose we investigated the prevalence and any possible associations of common TLR polymorphisms (TLR2-R753Q, TLR4-D299G, and TLR4-T399I) in a group of 240 heavy smokers (>20 pack years), without overt atherosclerosis disease, of whom 136 had developed COPD and 104 had not. The presence of TLR4-T399I polymorphism was associated with a 2.4-fold increased risk for COPD development (P = .044), but not with disease stage or frequency of exacerbations. Considering that infections contribute to COPD and emphysema pathogenesis, our findings possibly indicate that dysfunctional polymorphisms of innate immune genes can affect the development of COPD in smokers. Although this finding warrants further investigation, it highlights the importance of impaired innate immunity towards COPD development.
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PMID:Association of TLR4-T399I polymorphism with chronic obstructive pulmonary disease in smokers. 2016 3

Matrix metalloproteinases (MMPs) have a great variability that provides a complex intervention in pathophysiological conditions. MMPs roles in pathology may be grouped into the following main types: (1) tissue destruction, as in cancer invasion and metastasis, rheumatoid arthritis, osteoarthritis, different types of ulcers, periodontal disease, brain injury and neuroinflammatory diseases; (2) fibrosis, as in liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, and multiple sclerosis; (3) weakening of matrix, as in dilated cardiomyopathy, epidermolysis bullosa, aortic aneurysm and restenotic lesions. Recent data also adds new MMPs functions in angiogenesis and apoptosis. Interesting opposite intervention in escaping mechanisms vs. antitumor defensive mechanisms had been also reported. As MMP-7 is expressed by tumor cells of epithelial and mesenchymal origin, it may be used as a biological marker of an aggressive phenotype and as a target of therapeutic intervention. MMPs play a pivotal role in the pathogenesis of arthritis, atherosclerosis, pulmonary emphysema, and endometriosis. Although MMP involvement in pathology is more than simple excessive matrix degradation, or an imbalance between them and their specific tissular inhibitors (TIMPs), MMP inhibition may be of therapeutic benefit, so synthetic MMPs inhibitors had been developed and are currently under clinical testing.
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PMID:Matrix metalloproteinases involvement in pathologic conditions. 2049 35

Matrix metalloproteinases (MMPs) (1,2) comprise a family of over 20 matrix degrading enzymes believed to be essential for normal development and physiologic tissue remodeling and repair. Abnormal expression of metalloproteinases has been implicated in many destructive processes, including tumor cell invasion and angiogenesis, arthritis, atherosclerosis, and arterial aneurysms. With respect to lung disease, MMPs have been associated with chronic obstructive pulmonary disease (COPD), acute lung injury, pulmonary fibrosis, and asthma. The role of MMPs in causation of pulmonary emphysema has been supported by transgenic mice overexpressing MMP-1 (3) and gene targeted mice lacking MMP-12 (4).
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PMID:Measurement of metalloproteinases. 2133 15

Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV(1) has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV(1) and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45-84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors. Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV(1) was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60-0.97, p = 0.02) but not proximal aortic calcification or proximal aortic distensibility (-0.04 mmHg(-1); 95%CI -0.16-0.09 mmHg(-1), p = 0.60). Percent emphysema was associated with neither measure. FEV(1) was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta.
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PMID:Pulmonary function is associated with distal aortic calcium, not proximal aortic distensibility. MESA lung study. 2149 32


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