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)

Alveolar destruction is a cardinal feature of emphysema but is not traditionally believed to contribute to the pathogenesis of "classical" asthma. However, the relationship between chronic obstructive pulmonary disease (COPD) and asthma is controversial and the variety of mechanisms that can mediate the alveolar destruction in emphysema have not been adequately defined. To address these issues, we used overexpression transgenic approaches to define the effects of Th1/Tc1 and Th2/Tc2 cytokines in the mature murine lung and compared findings in these transgenic systems to the effects of similar interventions after cigarette smoke (CS) exposure. In these experiments, the Th1/Tc1 and Th2/Tc2 cytokines IFN-gamma and interleukin (IL)-13, respectively, both caused emphysema. The IFN-gamma response was associated with neutrophilia but was not associated with mucus metaplasia or a major fibrotic response. In this setting, IFN-gamma was a potent stimulator of matrix metalloproteinases (MMPs), cathepsins, and CXC and other chemokines while inhibiting secretory leukocyte proteinase inhibitor (SLPI). Interestingly, IFN-gamma induced its destructive effects via at least two mechanisms, a CCR5/cathepsin-dependent and apoptosis-mediated pathway and an MMP-12-dependent/apoptosis-independent pathway. CS-induced inflammation, apoptosis, and emphysema were also induced by IFN-gamma- and CCR5-dependent mechanisms. In contrast, IL-13-induced emphysema was associated with eosinophilia, mucus metaplasia, and pulmonary fibrosis. In this setting, IL-13 stimulated MMPs, cathepsins, and a variety of CC chemokines while inhibiting alpha(1)-antitrypsin. A cathepsin-dependent apoptosis pathway also contributed to this remodeling response. Interestingly, abnormalities in vascular endothelial growth factor (VEGF) were also appreciated with VEGF(165) excess producing an asthmalike pulmonary response and IFN-gamma abrogating this response while inducing emphysematous alveolar destruction. These findings provide molecular support for both points of view in the British/Dutch hypothesis controversy regarding the relationship between asthma and COPD. They also highlight the complexity of the pathways that can induce alveolar destruction and suggest that there is a continuum, based on VEGF, between asthma and COPD.
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PMID:State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: insights from transgenic mice. 1692 Nov 26

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in the airways and pulmonary tissue. The chemokine receptor CCR6 and its ligand MIP-3alpha/CCL20 may be involved in the recruitment of these inflammatory cells. To investigate the role of CCR6 in the pathogenesis of COPD, we analyzed the inflammatory responses of CCR6 knockout (KO) and wild-type mice upon cigarette smoke (CS) exposure. Both subacute and chronic exposure to CS induced an increase in cells of the innate and adaptive immune system in the bronchoalveolar lavage, both in CCR6 KO and wild-type mice. However, the accumulation of dendritic cells, neutrophils, and T lymphocytes, which express CCR6, was significantly attenuated in the CCR6 KO mice, compared with their wild-type littermates. In the lung tissue of CCR6 KO mice, there was an impaired increase in dendritic cells, activated CD8(+) T lymphocytes, and granulocytes. Moreover, this attenuated inflammatory response in CCR6 KO mice offered a partial protection against pulmonary emphysema, which correlated with an impaired production of MMP-12. Importantly, protein levels of MIP-3alpha/CCL20, the only chemokine ligand of the CCR6 receptor, and MCP-1/CCL2 were significantly increased upon CS exposure in wild-type, but not in CCR6 KO mice. In contrast, CCR6 deficiency had no effect on the development of airway wall remodeling upon chronic CS exposure. These results indicate that the interaction of CCR6 with its ligand MIP-3alpha contributes to the pathogenesis of CS-induced pulmonary inflammation and emphysema in this murine model of COPD.
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PMID:Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. 1698 69

We have previously observed that mice exposed to cigarette smoke and treated with exogenous alpha(1)-antitrypsin (A1AT) were protected against the development of emphysema and against smoke-induced increases in serum TNF-alpha. To investigate possible mechanisms behind this latter observation, we cultured alveolar macrophages lavaged from C57 mice. Smoke-conditioned medium caused alveolar macrophages to increase secretion of macrophage metalloelastase (MMP-12) and TNF-alpha, and this effect was suppressed in a dose-response fashion by addition of A1AT. Macrophages from animals exposed to smoke in vivo and then lavaged also failed to increase MMP-12 and TNF-alpha secretion when the animals were pretreated with A1AT. Because proteinase activated receptor-1 (PAR-1) is known to control MMP-12 release, macrophages were treated with the G protein-coupled receptor inhibitor, pertussis toxin; this suppressed both TNF-alpha and MMP-12 release, while a PAR-1 agonist (TRAP) increased TNF-alpha and MMP-12 release. Smoke-conditioned medium caused increased release of the prothrombin activator, tissue factor, from macrophages. Hirudin, a thrombin inhibitor, and aprotinin, an inhibitor of plasmin, reduced smoke-mediated TNF-alpha and MMP-12 release, and A1AT inhibited both plasmin and thrombin activity in a cell-free functional assay. These findings extend our previous suggestion that TNF-alpha production by alveolar macrophages is related to MMP-12 secretion. They also suggest that A1AT can inhibit thrombin and plasmin in blood constituents that leak into the lung after smoke exposure, thereby preventing PAR-1 activation and MMP-12/TNF-alpha release, and decreasing smoke-mediated inflammatory cell influx.
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PMID:Alpha1-antitrypsin suppresses TNF-alpha and MMP-12 production by cigarette smoke-stimulated macrophages. 1754 Oct 9

Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and is involved in a number of physiological or pathological situations, such as conversion of plasminogen into angiostatin, allergic airway inflammation, vascular remodeling or alteration, as well as emphysema, and has been justified as a novel drug target. Here, we report the over-expression in Escherichia coil, purification and refolding of MMP-12 catalytic domain for NMR studies. The primary sequence of expressed protein was identified by means of MALDI-TOF MS, and was confirmed by the MALDI-TOF MS data of trypsin-digested peptides. A significantly optimized protocol has been worked out to prepare 15N and/or 13C-labeled MMP-12 catalytic domain, and the yield of the purified protein is estimated to 10-12 mg from 0.5L of M9 minimal media. Finally, the 15N-1H HSQC spectrum of uniformly 15N-labeled MMP-12 catalytic domain indicates the presence of well-ordered and properly folded protein in a monomeric form.
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PMID:Over-expression and refolding of isotopically labeled recombinant catalytic domain of human macrophage elastase (MMP-12) for NMR studies. 1760 47

The authors tested whether macrophage metalloelastase (MMP-12) and substance P (SP) were increased in the cigarette smoke (CS)-exposed female C3H/HeN mice with hypercapnic emphysema. The authors found that as compared to control (filtered air), 16 weeks of CS exposure significantly up-regulated mRNA and protein levels of MMP-12, the ratio of MMP-12/tissue inhibitor of matrix metalloproteinase-1, and SP/preprotachykinin-A (a precursor to SP) in the lungs. Importantly, a significant correlation was found between MMP-12 and SP, and between MMP-12/SP and the degrees of hypoxemia/hypercapnia denoted in CS-exposed mice. These data suggest a possible involvement of SP and MMP-12 in the pathogenesis of severe COPD.
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PMID:Cigarette smoke-induced hypercapnic emphysema in C3H mice is associated with increases of macrophage metalloelastase and substance P in the lungs. 1762 Jan 83

Chronic obstructive pulmonary disease (COPD) is a smoking-related disease that lacks effective therapies due partly to the poor understanding of disease pathogenesis. The aim of this study was to identify molecular pathways that could be responsible for the damaging consequences of smoking. To do this, we employed Gene Set Enrichment Analysis to analyze differences in global gene expression, which we then related to the pathological changes induced by cigarette smoke (CS). Sprague-Dawley rats were exposed to whole body CS for 1 day and for various periods up to 8 mo. Gene Set Enrichment Analysis of microarray data identified that metabolic processes were most significantly increased early in the response to CS. Gene sets involved in stress response and inflammation were also upregulated. CS exposure increased neutrophil chemokines, cytokines, and proteases (MMP-12) linked to the pathogenesis of COPD. After a transient acute response, the CS-exposed rats developed a distinct molecular signature after 2 wk, which was followed by the chronic phase of the response. During this phase, gene sets related to immunity and defense progressively increased and predominated at the later time points in smoke-exposed rats. Chronic CS inhalation recapitulated many of the phenotypic changes observed in COPD patients including oxidative damage to macrophages, a slowly resolving inflammation, epithelial damage, mucus hypersecretion, airway fibrosis, and emphysema. As such, it appears that metabolic pathways are central to dealing with the stress of CS exposure; however, over time, inflammation and stress response gene sets become the most significantly affected in the chronic response to CS.
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PMID:Comprehensive gene expression profiling of rat lung reveals distinct acute and chronic responses to cigarette smoke inhalation. 1772 Aug 75

Phosphodiesterase 4 (PDE4) is an intracellular enzyme specifically degrading cAMP, a second messenger exerting inhibitory effects on many inflammatory cells. To investigate whether GPD-1116 (a PDE4 inhibitor) prevents murine lungs from developing cigarette smoke-induced emphysema, the senescence-accelerated mouse (SAM) P1 strain was exposed to either fresh air or cigarette smoke for 8 wk with or without oral administration of GPD-1116. We confirmed the development of smoke-induced emphysema in SAMP1 [air vs. smoke (means +/- SE); the mean linear intercepts (MLI), 52.9 +/- 0.8 vs. 68.4 +/- 4.2 microm, P < 0.05, and destructive index (DI), 4.5% +/- 1.3% vs. 16.0% +/- 0.4%, P < 0.01]. Emphysema was markedly attenuated by GPD-1116 (MLI = 57.0 +/- 1.4 microm, P < 0.05; DI = 8.2% +/- 0.6%, P < 0.01) compared with smoke-exposed SAMP1 without GPD-1116. Smoke-induced apoptosis of lung cells were also reduced by administration of GPD-1116. Matrix metalloproteinase (MMP)-12 activity in bronchoalveolar lavage fluid (BALF) was increased by smoke exposure (air vs. smoke, 4.1 +/- 1.1 vs. 40.5 +/- 16.2 area/microg protein; P < 0.05), but GPD-1116 significantly decreased MMP-12 activity in smoke-exposed mice (5.3 +/- 2.1 area/microg protein). However, VEGF content in lung tissues and BALF decreased after smoke exposure, and the decrease was not markedly restored by oral administration of GPD-1116. Our study suggests that GPD-1116 attenuates smoke-induced emphysema by inhibiting the increase of smoke-induced MMP-12 activity and protecting lung cells from apoptosis, but is not likely to alleviate cigarette smoke-induced decrease of VEGF in SAMP1 lungs.
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PMID:Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 strain. 1799 91

Chronic obstructive pulmonary disease (COPD) is the 5(th) most prevalent disease worldwide leading to severe morbidity and mortality in developed countries. The disease is strongly associated with smoking, and can be characterized by progressive and irreversible deterioration in lung function and destruction of the lung parenchyma. We show here that infection with the hookworm Nippostrongylus brasiliensis results in deterioration in lung function, destruction of alveoli and long-term airways hyperresponsiveness, consistent with COPD and emphysema. N. brasiliensis infection leads to chronic low level hemorrhaging in the lung and the presence of hemosiderin-laden macrophages in the absence of an overt inflammatory infiltrate. Microarray analysis of gene expression in diseased lungs and quantitative RT-PCR analysis of purified macrophages revealed a state of prolonged tissue injury and the presence of alternatively activated macrophages producing MMP-12. Taken together, these data show that lung tissue damage caused by hookworm infection can result in the development of COPD and emphysema.
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PMID:Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages. 1820 42

Adiponectin is an adipocyte-derived collectin that acts on a wide range of tissues including liver, brain, heart, and vascular endothelium. To date, little is known about the actions of adiponectin in the lung. Herein, we demonstrate that adiponectin is present in lung lining fluid and that adiponectin deficiency leads to increases in proinflammatory mediators and an emphysema-like phenotype in the mouse lung. Alveolar macrophages from adiponectin-deficient mice spontaneously display increased production of tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase (MMP-12) activity. Consistent with these observations, we found that pretreatment of alveolar macrophages with adiponectin leads to TNF-alpha and MMP-12 suppression. Together, our findings show that adiponectin leads to macrophage suppression in the lung and suggest that adiponectin-deficient states may contribute to the pathogenesis of inflammatory lung conditions such as emphysema.
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PMID:Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice. 1842 18

Macrophage elastase (MMP-12) is a member of the family of matrix metalloproteinases (MMPs) and is active against multiple extracellular protein substrates such as elastin. Its effect on elastin is central to emphysema in the lung and photoaging of skin. Its expression in the skin increases on photodamaged skin and upon aging. Detecting and characterizing peptides cleaved in elastin, therefore, helps to understand such degradative disease processes in the skin and is also needed to assist in the rational design of agents that specifically inhibit the degradation. In this study, cleavage sites of MMP-12 in human skin elastin were extensively investigated. The peptides formed as a result of cleavages by this enzyme in the human skin elastin were characterized using mass spectrometry. A total of 41 peptides ranging from 4 to 41 amino acids were identified and 36 cleavage sites were determined. Amino acids encoded by exons 5, 6, 26, 28-31 were particularly susceptible to cleavages by MMP-12 and none or very few cleavages were detected from domains encoded by the remaining exons. The amino acid preferences of the different subsites on the catalytic domain of MMP-12 were analyzed.
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PMID:Mapping of macrophage elastase cleavage sites in insoluble human skin elastin. 1833 88


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