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)

Members of the matrix metalloproteinase family of enzymes degrade specific components of the extracellular matrix. MMP-9 is a type IV/V collagenase necessary for normal osteogenesis and is increased in inflammatory and neoplastic conditions. In such destructive diseases as emphysema and arthritis, and in epithelial cancers, MMP-9 is produced by cells of the monocyte lineage. Fetuin, a prominent serum glycoprotein, binds to and inactivates TGF-beta family members and through this mechanism regulates osteogenesis (Binkert et al., 1999, J Biol Chem 274:28514-28520.). We studied the effects of TGF-beta1 and fetuin on proMMP-9 release by the human monocyte line THP-1. Exogenous TGF-beta1 stimulated proMMP-9 release by THP-1 cells, with half-maximal stimulation at approximately 0.01 ng/ml TGF-beta1. Human fetuin (0.5-2 microM) partially inhibited this stimulation. Human fetuin alone stimulated THP-1 monocyte proMMP-9 release, with half maximal stimulation at approximately 0.25 microM fetuin. Neutralizing antibody specific for TGF-beta1 also stimulated proMMP-9 release, suggesting that endogenously-derived TGF-beta1 has an inhibitory effect. In freshly isolated human peripheral blood monocytes, fetuin stimulated proMMP-9 release with a dose-response curve similar to that observed in THP-1 cells. Human fetuin also activated proMMP-9 present in THP-1 conditioned medium. Taken together, these data suggest that under physiological conditions, fetuin facilitates matrix degradation by monocyte-derived MMP-9, both by opposing the autocrine inhibitory effect of endogenous TGF-beta1 on proMMP-9 release, and by activating proMMP-9 in the pericellular milieu. Conversely, fetuin may limit the stimulation of monocyte proMMP-9 release by high levels of exogenous TGF-beta1. Such modulation could prove important under pathological conditions where TGF-beta1 derived from paracrine sources is abundant, such as in epithelial malignancies.
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PMID:Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-beta antagonist. 1102 39

Expression microarrays are a powerful tool that could provide new information about the molecular pathways regulating common lung diseases. To exemplify how this tool can be useful, selected examples of informative experiments are reviewed. In studies relevant to asthma, the cytokine interleukin-13 has been shown to produce many of the phenotypic features of this disease, but the cellular targets in the airways and the molecular pathways activated are largely unknown. We have used microarrays to begin to dissect the different transcriptional responses of primary lung cells to this cytokine. In experiments designed to identify global transcriptional programs responsible for regulating lung inflammation and pulmonary fibrosis, we performed microarray experiments on lung tissue from wild-type mice and mice lacking a member of the integrin family know to be involved in activation of latent transforming growth factor (TGF)-beta. In addition to identifying distinct cluster of genes involved in each of these processes, these studies led to the identification of novel pathways by which TGF-beta can regulate acute lung injury and emphysema. Together, these examples demonstrate how careful application and thorough analysis of expression microarrays can facilitate the discovery of novel molecular targets for intervening in common lung diseases.
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PMID:Roger S. Mitchell lecture. Uses of expression microarrays in studies of pulmonary fibrosis, asthma, acute lung injury, and emphysema. 1189 58

Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that are secreted as inactive (latent) precursors in large protein complexes. These complexes include the latency-associated propeptide (LAP) and a latent transforming growth factor-beta binding protein (LTBP). Four isoforms of LTBPs (LTBP-1-LTBP-4) have been cloned and are believed to be structural components of connective tissue microfibrils and local regulators of TGF-beta tissue deposition and signaling. By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, we have disrupted the mouse homolog of the human LTBP-4 gene. Mice homozygous for the disrupted allele develop severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities are associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF-beta in the extracellular space. As a consequence, epithelial cells have reduced levels of phosphorylated Smad2 proteins, overexpress c-myc, and undergo uncontrolled proliferation. This phenotype supports the predicted dual role of LTBP-4 as a structural component of the extracellular matrix and as a local regulator of TGF-beta tissue deposition and signaling.
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PMID:Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. 1220 49

Sustained oxidative stress caused by cigarette smoking induces a chronic inflammatory response, resulting in the destruction of the alveolar cell wall characteristic of emphysema. The loss of tissue may involve the progressive depletion of epithelial cells through inhibition of proliferation leading to cell death. The cell cycle regulator p21(waf1/cip1) acts as a G(1)/S and G(2)/M phase checkpoint regulator. We hypothesize that cigarette smoke-induced oxidative stress and transforming growth factor beta 1 (TGF-beta(1)) may inhibit cellular proliferation by p21(waf1/cip1) in type II alveolar epithelial cells (A549). A significant increase was observed in p21(waf1/cip1) mRNA expression in A549 cells by cigarette smoke condensate, H(2)O(2), and TGF-beta(1). In conclusion, cigarette smoke-induced oxidative stress and TGF-beta(1) modulate expression of the cell cycle inhibitor p21(waf1/cip1). This may be important in the growth arrest and cell survival of alveolar type II cells in the G(1) phase.
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PMID:Cigarette smoke-induced oxidative stress and TGF-beta1 increase p21waf1/cip1 expression in alveolar epithelial cells. 1248 77

Delivery of genes to the pulmonary vascular endothelium is a rational approach for the investigation and potential therapy of pulmonary vascular diseases. Furthermore, in view of the exposure of this vascular bed to the entire cardiac output, this technique could be used as an efficient basis to achieve systemic delivery of secreted factors. The attraction of direct gene delivery to endothelium for the therapy of vascular disease has been especially heightened in the last couple of years in view of the new discoveries concerning the genetic basis of primary pulmonary hypertension (PPH). In brief, mutations in the bone morphogenetic protein receptor type 2 (BMPR2, a member of the transforming growth factor-beta [TGF-beta] family of receptors) gene have been found in many patients with familial PPH. Subsequent in vitro studies have confirmed an association between BMPR2 mutations and abnormal proliferative responses in pulmonary endothelial and smooth-muscle cells (2). Other TGF-beta signaling pathways may also be involved in this process, and the mechanisms involved may also have relevance for the more common cases of pulmonary vascular disease secondarily associated with chronic airways obstruction, connective tissue diseases, and perhaps HIV infection. Additionally, new evidence is emerging concerning the role of the vasculature in the pathogenesis of emphysema.
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PMID:Delivery of DNA to pulmonary endothelium using adenoviral vectors. 1497 May 86

The five integrins that contain the alphav subunit are widely expressed and their expression is tightly regulated. However, most tissues in mice lacking the alphav subunit, and thus deficient in all five integrins, develop normally, suggesting that nearly all of the critical steps in development and cellular differentiation can occur in the absence of these integrins. Studies over the past few years have identified highly specialized roles for specific alphav integrins in preventing inappropriate vascular growth and in control of vascular permeability. Two members of this family, alphavbeta6 and alphavbeta8, play novel roles in activating latent complexes of the growth factor TGFbeta (transforming growth factor beta). Studies in mice lacking the beta6 subunit have identified unexpected roles for alphavbeta6-mediated TGFbeta activation in models of pulmonary and renal fibrosis, acute lung injury and pulmonary emphysema.
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PMID:Roles of alphav integrins in vascular biology and pulmonary pathology. 1536 6

Latent transforming growth factor (TGF)-beta binding proteins (LTBPs) modulate the secretion and activation of latent TGF-beta. To explore LTBP function in vivo, we created an Ltbp-3(-/-) mouse that has developmental emphysema with decreased septation in terminal alveoli. Differences in distal airspace enlargement were obvious at day 6 after birth. Secondary septation was inhibited, so by days 21 to 28 the mean linear intercept was approximately twofold greater in mutant versus control lungs. There were no differences in lung collagen and elastin, visualized by immunohistochemistry, or in myofibroblast numbers, determined by alpha-smooth muscle actin-positive cells, between mutant or wild-type lungs as the animals aged, other than differences associated with altered lung structure in mutant animals. However, from day 10 there was twice the number of alveolar type II cells in mutant alveoli compared to controls. At days 6 and 10, a transient enhancement in cell proliferation in the mutant lungs was observed by both 5-bromo-2'-deoxy-uridine and proliferating cell nuclear antigen labeling, accompanied by enhanced numbers of terminal dUTP nick-end labeling-positive cells at days 4, 6, and 10. Finally, there was a transient decrease in TGF-beta signaling at days 4 to 6 in Ltbp-3(-/-) lungs. These results indicate that in the absence of Ltbp-3, a temporary decrease in TGF-beta signaling in the lungs at days 4 to 6 alters cell proliferation, correlating with inhibition of septation and developmental emphysema.
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PMID:Lung alveolar septation defects in Ltbp-3-null mice. 1604 28

Members of the integrin family recognize a variety of spatially-restricted extracellular ligands. Classically, ligation of integrins activates cytoplasmic signals in the integrin-expressing cell and contributes to cell adhesion, migration, proliferation and survival. At least two members of this family, alphavbeta6 and alphavbeta8 perform an additional function, activation of latent complexes of transforming growth factor beta. In effect, this process allows integrins on one cell to activate signals on adjacent (in the case of alphavbeta6) or nearby cells (in the case of alphavbeta8). Integrin-mediated TGFbeta activation has been shown to play important roles in modulating tissue fibrosis, acute lung injury and pulmonary emphysema. Given the important roles that TGFbeta plays in modulating epithelial cell growth, epithelial-to-mesenchymal transformation and tumor invasion and metastasis, integrin-mediated TGFbeta activation is likely to play important roles in tumor growth and metastasis.
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PMID:Integrin-mediated activation of latent transforming growth factor beta. 1625 27

Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938-18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-alpha-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-beta signaling, because TGF-beta type I receptor kinase inhibitor or TGF-beta neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is >24 h, but it is decreased to approximately 8 h by addition of TGF-beta neutralizing antibody, EGF, TGF-alpha, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-alpha is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-beta signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-beta-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.
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PMID:Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts. 1647 61

Pulmonary emphysema, as a feature of chronic obstructive pulmonary disease (COPD), is characterised by destruction of alveolar tissue. The present authors previously demonstrated reduced decorin expression in the peribronchial area of COPD patients, reflecting an altered extracellular matrix (ECM) modulation. Decorin transcription is regulated by the transforming growth factor (TGF)-beta-Smad pathway, the key intracellular signal route for initiation of ECM component gene transcription. Whether this pathway is aberrantly expressed in COPD is not known. An immunohistochemical study was performed to compare protein expression of TGF-beta1 and TGF-beta receptors, Smad 2, 3, 4 and 7, and decorin in lung tissue of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II and IV COPD patients and controls. Epithelial expression of the inhibitory Smad 7 was significantly lower in patients with GOLD stages II and IV than in controls, with other Smad protein expressions being similar in the groups. The expression of TGF-beta1 and TGF-beta receptor type I was significantly lower in stage II patients. Decorin staining of the adventitia and alveolar walls was significantly reduced in COPD stage IV. In conclusion, the transforming growth factor-beta-Smad pathway is aberrantly expressed in chronic obstructive pulmonary disease patients, implying an abnormal tissue repair ultimately resulting in reduced decorin production. The results of the present study contribute to better understanding of the pathogenesis of emphysema and the airway fibrosis observed in chronic obstructive pulmonary disease patients.
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PMID:Altered expression of the Smad signalling pathway: implications for COPD pathogenesis. 1670 15


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