Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibulin-5, previously known as DANCE and EVEC, is a secreted extracellular matrix protein that functions as a scaffold for elastin fiber assembly and as a ligand for integrins alphavbeta3, alphavbeta5, and alpha9beta1. Fibulin-5 is developmentally regulated in the lung, and lung air space enlargement develops in mice deficient in fibulin-5. Fibulin-5 is also induced in adult lung following lung injury by hyperoxia. To further examine the role of fibulin-5 during repair of lung injury, we assessed fibulin-5 expression during elastase-induced emphysema in C57/b mice. Mice were treated with either saline or elastase via the trachea, and the lung was examined 20 days after treatment. Fibulin-5 mRNA was induced almost fourfold, whereas elastin mRNA was minimally elevated. Immunohistochemistry studies showed that fibulin-5 was induced in cells within the alveolar wall following elastase treatment. Western analysis demonstrates that fibulin-5 was strongly expressed in isolated primary lung interstitial fibroblasts. Fibulin-5 protein was localized to the fibroblast cell layer in culture, and brief elastase treatment degraded the protein. Intact fibulin-5 did not accumulate in the culture media. Treatment of fibroblasts with the proinflammatory cytokine interleukin-1beta abolished fibulin-5 mRNA expression. Our results indicate that fibulin-5 is coordinately expressed and regulated with elastin in lung fibroblasts and may serve a key role during lung injury and repair.
Am J Physiol Lung Cell Mol Physiol 2003 Nov
PMID:Coordinate expression of fibulin-5/DANCE and elastin during lung injury repair. 1290 85

Cumulative evidence has shown that a delicate balance between serine proteases and their inhibitors is crucial for normal functioning of several biological pathways. The importance of proteases and their inhibitors is well documented in several human diseases. Among them, the best documented are hemophilia B, a genetic deficiency of the serine protease coagulation factor IX and serpinophathies. Alpha-1-antitrypsin deficiency (MIM 107400), is associated with early-onset emphysema and liver disease, while hereditary angioedema (HANE; MIM 106100) is caused by mutations in the C1 inhibitor, a serpin involved in the regulation of the complement cascade. Recently, two human genetic diseases of the central nervous system have been related to mutations in components of extracellular proteolytic systems. Here, we review the recent advances in this field.
Hum Mol Genet 2003 Oct 15
PMID:Extracellular proteases and their inhibitors in genetic diseases of the central nervous system. 1292 75

Gene transfer to the lung could provide important new treatments for chronic and acquired lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency, emphysema, and cancer. DNA-mediated gene transfer to the lung has been previously demonstrated, but anticipated effectiveness has been limited by low gene transfer efficiencies and by transient expression of the transgene. Here, we combine plasmid-based gene transfer with the integrating capacity of the nonviral Sleeping Beauty (SB) transposon vector system to mediate gene insertion and long-term gene expression in mouse lung. We observed transgene expression after 24 h in lungs of all animals injected with the luciferase transposon (pT/L), but expression for up to 3 months required codelivery of a plasmid encoding the Sleeping Beauty transposase. We also observed long-term expression in pT/L-injected animals transgenic for SB transposase. Transgene expression was localized to the alveolar region of the lung, with transfection including mainly type II pneumocytes. We used a linker-mediated PCR technique to recover transposon flanking sequences, demonstrating transposition of pT/L into mouse chromosomal DNA of the lung.
Mol Ther 2003 Sep
PMID:Gene insertion and long-term expression in lung mediated by the Sleeping Beauty transposon system. 1294 24

To develop a model in which the pathogenic effects of the proinflammatory cytokine tumor necrosis factor-alpha (TNF) could be investigated, transgenic mice that express TNF in the lung under the control of a doxycycline-inducible promoter were generated. TNF transgene message was expressed at a low level in the absence of doxycycline treatment and was induced in the lung by administration of the drug. Analysis of lung lavage fluid indicated increases in neutrophils and lymphocytes in doxycycline-treated transgenic mice. Histologic analysis of lungs from adult transgenic mice treated with doxycycline revealed prominent development of lymphoid tissue and increases in airspace size. Genes upregulated in TNF transgenic mice, as identified by oligonucleotide microarray analysis, included a variety of transcripts expressed in lymphoid tissues. Immunohistochemical analysis demonstrated the presence of B lymphocytes and, to a lesser extent, T lymphocytes within lymphoid aggregates in TNF transgenic mice. CD8-positive T cells were absent from lymphocytic nodules, but in the lung parenchyma were more abundant in transgenic than in nontransgenic mice. These results indicate that induction of TNF in adult lung promotes the formation of lymphoid tissue and emphysema, and provides a model in which the pathogenic effects of TNF on the lung can be investigated.
Am J Respir Cell Mol Biol 2004 Apr
PMID:Lymphoid tissue and emphysema in the lungs of transgenic mice inducibly expressing tumor necrosis factor-alpha. 1297 99

Matrix metalloproteinases (MMPs) are a family of neutral proteinases that are important for normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, pulmonary fibrosis, emphysema and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood brain barrier and to contribute to the neuroinflammatory responses in many neurological diseases. Inhibition of MMPs have been shown to prevent progression of these diseases. Currently, certain MMP inhibitors have entered into clinical trials. A goal to the future should be to design selective synthetic inhibitors of MMPs that have minimum side effects. MMP inhibitors are designed in such a way that these can not only bind at the active site of the proteinases but also to have the characteristics to bind to other sites of MMPs which might be a promising route for therapy. To name a few: catechins, a component isolated from green tea; and Novastal, derived from extracts of shark cartilage are currently in clinical trials for the treatment of MMP-mediated diseases.
Mol Cell Biochem 2003 Oct
PMID:Clinical implications of matrix metalloproteinases. 1457 6

The functional roles of neutral lipids are poorly understood in the lung. Blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal-/-) resulted in a high level of neutrophil influx in the lungs as early as 2 mo of age. Bronchoalveolar macrophages appeared foamy and gradually increased in number with age progression. Affymetrix GeneChip array analysis of lung mRNA showed increased levels of proinflammatory cytokine (including IL-1beta, IL-6, and TNF-alpha) and matrix metalloproteinase (including MMP-8, MMP-9, and MMP-12) expression in lal-/- mice. With age progression, some areas of lal-/- mice developed severe abnormal cell proliferation and alveolar remodeling. In other areas, alveolar destruction (i.e., emphysema) was observed. In addition, Clara cell hypertrophy and hyperplasia developed in conducting airways. The pathophysiological phenotypes in the lal-/- mouse lungs became more severe with increasing age. The studies support the concept that neutral lipid metabolites play essential roles in pulmonary homeostasis, inflammatory responses, remodeling, and injury repair.
Am J Physiol Lung Cell Mol Physiol 2004 Apr
PMID:Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung. 1464 59

Matrix metalloproteinases (MMPs) are an at least 23 member family of calcium and zinc dependent enzymes implicated in many physiological and pathological processes. Asthma, chronic obstructive pulmonary disease (COPD) and emphysema are diseases associated with an inflammation of the airways and lung parenchyma. In this review, we focus on the role played by MMPs in the pathogenesis of inflammation, airway remodelling and alveolar destruction, depicting the observational studies in humans and the experimental studies in animal models. During the course of asthma, MMP-2,-8,-9 and TIMP-1 are expressed at baseline and the allergen exposure or exacerbations of the disease lead to an increase of MMP-9 secretion being at this time much higher than that of TIMP-1, allowing temporarily a matrix damage, possibly followed by abnormal repair. Animal models suggest a predominant role for MMP-9 and MMP-12 in the pathogenesis of pulmonary inflammation and link an absence of MMP-2 to an increased parenchymal inflammation. In COPD and emphysema, human studies indicate an over-secretion of MMP-2,-8,-9 and animal models pointout MMP-1 and MMP-12 as being key players in the pathogenesis of emphysema. Taken together, these data identify specific MMP inhibition as appropriate target for therapeutic intervention in asthma or COPD/emphysema They also strongly argue against the widespread use of large spectrum non specific inhibitors that could be detrimental.
Cell Mol Biol (Noisy-le-grand) 2003 Sep
PMID:Pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix metalloproteases inhibitors. 1465 45

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.
Methods Mol Biol 2004
PMID:Delivery of DNA to pulmonary endothelium using adenoviral vectors. 1497 May 86

The Z variant of alpha1-antitrypsin (Z-AT) is present in 4% of Northern Europeans and is associated with liver cirrhosis and emphysema. Polymers accumulate within the hepatocyte and the subsequent plasma deficiency of AT renders the lungs susceptible to proteolysis and early onset emphysema. We have previously demonstrated that the Phe-Leu-Glu-Ala-Ile-Gly (6 mer) peptide specifically binds to Z-AT and inhibits polymerization. Here we present the first detailed biochemical study of the purified Z-AT-6 mer binary complex. Biochemical studies indicated that this complex was inactive as a proteinase inhibitor and the peptide annealed to beta-sheet A of Z-AT. Removal of the N-acetyl terminus of the 6 mer peptide did not affect the peptide's ability to prevent polymer formation. However, the nonacetylated 6 mer-Z-AT complex dissociated at a rate 2.75 x faster than the acetylated 6 mer-Z-AT complex to yield an active inhibitor; Koff 5.5 +/- 1.07 versus 2.0 +/- 0.25 10(6) s(-1), respectively. These biochemical data indicate a potential therapeutic approach whereby polymerization is prevented in the liver, with the gradual release of the peptide from the binary complex restoring proteinase inhibitory function within the tissues. Thus, it raises the novel prospect of ameliorating both the cirrhosis and the emphysema associated with Z-AT.
Am J Respir Cell Mol Biol 2004 Aug
PMID:Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin-related emphysema. 1501 19

To determine whether increased levels of VEGF disrupt postnatal lung formation or function, conditional transgenic mice in which VEGF 164 expression was enhanced in respiratory epithelial cells were produced. VEGF expression was induced in the lungs of VEGF transgenic pups with doxycycline from postnatal day 1 through 2 and 6 wk of age. VEGF levels were higher in bronchoalveolar lavage fluid (BALF) and lung homogenates of VEGF transgenic mice compared with endogenous VEGF levels in controls. Neonatal mortality was increased by 50% in VEGF transgenic mice. Total protein content in BALF was elevated in VEGF transgenic mice. Surfactant protein B protein expression was unaltered in VEGF transgenic mice. Although postnatal alveolar and vascular development were not disrupted by VEGF expression, VEGF transgenic mice developed pulmonary hemorrhage, alveolar remodeling, and macrophage accumulation as early as 2 wk of age. Electron microscopy demonstrated abnormal alveolar capillary endothelium in the VEGF transgenic mice. In many locations, the endothelium was discontinuous with segments of attenuated endothelial cells. Large numbers of hemosiderin-laden macrophages and varying degrees of emphysema were observed in adult VEGF transgenic mice. Overexpression of VEGF in the neonatal lung increased infant mortality and caused pulmonary hemorrhage, hemosiderosis, alveolar remodeling, and inflammation.
Am J Physiol Lung Cell Mol Physiol 2004 Jul
PMID:VEGF causes pulmonary hemorrhage, hemosiderosis, and air space enlargement in neonatal mice. 1503 36


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