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)

Alpha1-antitrypsin (alpha1AT) therapy is used as a treatment for alpha1AT deficiency. It has also been proposed as a therapy for cigarette smoke-induced emphysema, although the efficacy of such therapy is as yet unproven. Moreover, the optimal route of delivery of alpha1AT to the lung interstitium, the crucial locus of action, is unknown. We created transgenic mice with expression of the human alpha1AT gene directed by a human surfactant protein C (SpC) promoter fragment or a rat Clara cell 10-kDa protein (CC10) promoter fragment in order to examine the ability of pulmonary epithelial cell expression of alpha1AT to deliver protein to the interstitium, and to produce a model that would allow studies on the efficacy of alpha1AT in preventing lung damage after cigarette smoke exposure. Four transgenic lines were studied. In situ hybridization and light microscopic immunohistochemistry showed that two CC10 driven lines expressed human alpha1AT in type 11 alveolar cells and airway epithelial cells; alpha1AT expression was seen in the alveolar parenchyma in two SpC driven lines, and in small airway epithelium in one of the SpC lines. Electron microscopic immunochemistry showed the presence of the human alpha1AT protein in the interstitium in all lines. Mean levels of human protein varied from 0.37 to 2.9 microg/g lung protein and serum levels from 0.72 to 1.3 microg/ml, compared to normal human serum alpha1AT levels of 2-5 mg/ml. We conclude that transgene-mediated expression of alpha1AT in pulmonary epithelial cells results in diffuse expression of the transgene in the alveolar parenchyma and reproducibly leads to transfer of protein to the interstitium. The present model is, however, limited by low levels of protein production; limited protein production may be a problem in other forms of gene therapy in which relatively large amounts of extracellular protein are needed in the lung for a therapeutic effect.
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PMID:Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice results in delivery of alpha1-antitrypsin protein to the interstitium. 1035 39

Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease. To further explore the role of PDGF in these processes, we have developed transgenic mice that express the PDGF-B gene from the lung-specific surfactant protein C (SPC) promoter. Adult SPC-PDGFB transgenic mice exhibited lung pathology characterized by enlarged airspaces, inflammation, and fibrosis. Emphysematous changes frequently occurred throughout the lung, but inflammation and fibrotic lesions were usually confined to focal areas. The severity of this phenotype varied significantly among individual mice within the same SPC-PDGFB transgenic lineage. A pathology similar to that observed in adult mice was noted in lungs from transgenic mice as young as 1 week of age. Neonatal transgenic mice exhibited enlarged saccules and thickened primary septa. Results of these studies indicated that overexpression of PDGF-B induced distinct abnormalities in the developing and adult lung and led to a complex phenotype that encompassed aspects of both emphysema and fibrotic lung disease.
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PMID:Emphysematous lesions, inflammation, and fibrosis in the lungs of transgenic mice overexpressing platelet-derived growth factor. 1036 1

Tumor necrosis factor (TNF)-alpha is a key proinflammatory cytokine that is thought to be important in the development of pulmonary fibrosis, whereas its role in pulmonary emphysema has not been as thoroughly documented. In the present study, TNF-alpha was overexpressed in alveolar type II cells under the control of the human surfactant protein C promoter. In this report, we further characterized the pulmonary abnormalities and provided a physiological assessment of these mice. Histopathology of the lungs revealed chronic inflammation, severe alveolar air space enlargement and septal destruction, and bronchiolitis. However, pulmonary fibrosis was very limited and only seen in the subpleural, peribronchiolar, and perivascular regions. Physiological assessment showed an increase in lung volumes and a decrease in elastic recoil characteristic of emphysema; there was no evidence of restrictive lung disease characteristic of pulmonary fibrosis. In addition, the mice raised in ambient conditions in Denver developed pulmonary hypertension. Gelatinase activity was increased in the lavage fluid from these lungs. These results suggest that in these mice TNF-alpha contributed to the development of pulmonary emphysema through chronic lung inflammation and activation of the elastolytic enzymes but by itself was unable to produce significant pulmonary fibrosis.
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PMID:Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. 1113 93

Transgenic mice overexpressing human transforming growth factor-alpha (TGF-alpha) develop emphysema and fibrosis during postnatal alveologenesis. To assess dose-related pulmonary alterations, four distinct transgenic lines expressing different amounts of TGF-alpha in the distal lung under control of the surfactant protein C (SP-C) promoter were characterized. Mean lung homogenate TGF-alpha levels ranged from 388 +/- 40 pg/ml in the lowest expressing line to 1,247 +/- 33 pg/ml in the highest expressing line. Histological assessment demonstrated progressive alveolar airspace size changes that were more severe in the higher expressing TGF-alpha lines. Pleural and parenchymal fibrosis were only detected in the highest expressing line (line 28), and increasing terminal airspace area was associated with increasing TGF-alpha expression. Hysteresis on pressure-volume curves was significantly reduced in line 28 mice compared with other lines of mice. There were no differences in bronchoalveolar lavage fluid cell count or differential that would indicate any evidence of lung inflammation among all transgenic lines. Proliferating cells were increased in line 28 without alterations of numbers of type II cells. We conclude that TGF-alpha lung remodeling in transgenic mice is dose dependent and is independent of pulmonary inflammation.
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PMID:Dose-dependent lung remodeling in transgenic mice expressing transforming growth factor-alpha. 1159 99

Although fibroblast growth factor (FGF) signaling is required for the formation of the lung in the embryonic period, it is unclear whether FGF receptor activity influences lung morphogenesis later in development. We generated transgenic mice expressing a soluble FGF receptor (FGFR-HFc) under conditional control of the lung-specific surfactant protein C promoter (SP-C-rtTA), to inhibit FGF activity at various times in late gestation and postnatally. Although expression of FGFR-HFc early in development caused severe fetal lung hypoplasia, activation of the transgene in the postnatal period did not alter alveolarization, lung size, or histology. In contrast, expression of the transgene at post-conception day E14.5 decreased lung tubule formation before birth and caused severe emphysema at maturity. FGFR-HFc caused mild focal emphysema when expressed from E16.5 but did not alter alveolarization when expressed after birth. Although FGF signaling was required for branching morphogenesis early in lung development, postnatal alveolarization was not influenced by FGFR-HFc.
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PMID:Prenatal, but not postnatal, inhibition of fibroblast growth factor receptor signaling causes emphysema. 1239 66

Although genetic factors are assumed to have a role in the etiology of respiratory distress syndrome (RDS), specific genes underlying this susceptibility are incompletely known. The most promising candidates are the genes coding for the lung-specific protein components of the surfactant. In congenital absence of surfactant protein A in mice, lung mechanics or surfactant homeostasis is normal. However, there is an increased susceptibility to infections. The major surfactant protein A alleles, 6A(2) and 1A(0), are the general high-risk RDS alleles, while the allele 6A(3) carries a decreased risk of RDS. The allele 6A(6) is also over-represented in infants with bronchopulmonary dysplasia. To date, no human infants who lack surfactant protein A have been identified, and the human respiratory phenotype associated with the 1A(0) allele has been demonstrated to be variable, therefore, surfactant protein A polymorphisms are not currently useful for estimation of individual risk of having an affected infant. Surfactant protein B (SP-B) plays an essential role in the structure of tubular myelin. Mutations resulting in an absence of surfactant protein B have been identified. They cause a recessively inherited, progressive respiratory disease. More than 27 loss of function mutations have been identified in the surfactant protein B gene that result in lethal neonatal respiratory failure. Of the several known common variants of the surfactant protein B gene, the most common mutation is 121ins22 that accounts for 60-70% of the mutant cases. Although the frequency of the 121ins2 mutation is rare, the consistent phenotype is exhibited by infants with a homozygous genotype. The clinical presentation in infants homozygous for the 121ins2 mutation is full-term infants who develop respiratory distress within the first 12-24 hours of life. Surfactant replacement therapy fails to reverse this outcome, and without lung transplantation, they expire within the first 1-6 months of life. Surfactant protein B gene mutations may also result in milder phenotypes. These mutations resulting in reduced synthesis of SP-B appear to be family-specific and result in respiratory distress, but sometimes with more gradually progressive or chronic respiratory failure. Surfactant protein C plays a role in the stabilization of surfactant and may also have a role in the intracellular processing of the surfactant complex. Surfactant protein B is important in the intracellular processing and production of surfactant protein C. Although surfactant protein C-deficient mice are viable and survive to adulthood without obvious pulmonary abnormalities, their lung have reduced viscoelasticty. Human respiratory disease in the neonatal period caused by loss-of-function mutations in the surfactant protein C gene has not been identified. However, an autosomal dominant inherited mutation at the surfactant protein C gene causes chronic interstitial lung disease. Surfactant protein D is a member of the collectin family like surfactant protein A, therefore it opsonizes pathogens and enhances their phagocytosis by alveolar macrophages and neutrophils. Unlike surfactant protein A, it does not contribute to lowering surface tension. Surfactant protein D-deficient mice have no respiratory abnormalities at birth, but it causes development of emphysema and predisposition to specific infections. No human infant or child with respiratory distress and mutation in the surfactant protein D gene has been identified.
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PMID:Inherited disorders of neonatal lung diseases. 1521 37

The doxycycline-inducible, gene regulatory system allows tight control of transgene expression for the study of organ development and disease pathogenesis. Multiple recent reports have employed this model to investigate various lung diseases including emphysema. For our study, we used this transgenic system to test whether prolonged, lung-specific, overexpression of the serine protease urokinase plasminogen activator (uPA) would result in alveolar wall destruction. Double transgenic mice were generated that possessed: (1) the rat Clara cell secretory protein promoter controlling the reverse tetracycline transactivator gene (CCSP:rtTA) and (2) the tetracycline operator controlling the murine uPA cDNA (tet[O]:muPA). Mice were treated with doxycycline beginning at age 6 wk to initiate uPA overexpression. Single transgenic and wild-type animals served as controls. A second group of double transgenic and control animals were maintained off of doxycycline. At ages 10, 18, and 30 wk, the mice underwent measurements of alveolar size, lung compliance, and total lung capacity. We found that, although the uPA overexpressing mice demonstrated an emphysema phenotype, similar abnormalities occurred in the CCSP-rtTA control animals. These CCSP-rtTA-related alterations occurred even without doxycycline exposure. Evaluation of a second transgenic line possessing the human surfactant protein C promoter controlling rtTA expression also exhibited lung abnormalities consistent with emphysema. These findings indicate that pulmonary epithelial expression of rtTA alone causes an emphysema phenotype in mice. Therefore, when using this system to study emphysema pathogenesis, the inclusion of proper controls is essential for accurate data interpretation.
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PMID:Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice. 1661 85

Surfactant proteins (SP)-A and -D are members of the collectin family of host defense proteins that share four distinct structural domains: NH(2)-terminal oligomerization, collagenous, neck, and carbohydrate recognition (CRD). To determine the specificity of the functions of these domains, the SFTPC promoter was used to express 1) full-length rat (r) Sftpa; 2) NH(2)-rSftpa/d, consisting of NH(2)-terminal and collagenous domains of SP-A with neck domain and CRD of SP-D; and 3) rSftpd/a, consisting of NH(2)-terminal and collagenous domains of SP-D with neck domain and CRD of SP-A, in Sftpd(-/-) mice. Increased expression of SP-A in Sftpd(-/-) mice did not correct the increased pulmonary saturated phosphatidylcholine levels, emphysema, or foamy alveolar macrophage and lymphocyte infiltrations characteristic of Sftpd(-/-) mice, indicating that the decreased SP-A level noted in Sftpd(-/-) mice does not account for the observed pulmonary abnormalities. The chimeric protein NH(2)-rSftpa/d was expressed and detected in the airways of transgenic mice, migrating as an SP-A-like oligomer that associated with large aggregate surfactant in a manner similar to that of SP-A rather than SP-D. NH(2)-rSftpa/d did not correct emphysema, foamy macrophage and lymphocyte infiltration, or the increased lipid accumulations characteristic of Sftpd(-/-) mice. Thus oligomerization and surfactant lipid association of SP-D requires its NH(2)-terminal and collagenous domains, which are needed for SP-D-dependent regulation of surfactant homeostasis in vivo. Attempts to express rSftpd/a fusion protein in vivo were unsuccessful. Mmp9(-/-)/Sftpd(-/-) and Mmp12(-/-)/Sftpd(-/-) mice developed air space enlargement similar to Sftpd(-/-) mice, supporting the concept that the increased expression of each metalloproteinase seen in Sftpd(-/-) lungs is not the major cause of emphysema.
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PMID:Neither SP-A nor NH2-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis. 1650 Sep 46

Mutations in the gene encoding surfactant protein C (SP-C) SFTPC have been found to be associated with chronic interstitial lung disease. A 5-year-old girl oxygen dependent from birth and affected by interstitial lung disease (ILD) is heterozygous for a T to C change in exon 3 resulting in the substitution of threonine for isoleucine at codon 73 (173T), already described in association with ILD. We studied 25 members of her family where the 173T mutation in the SP-C gene is associated to chronic pulmonary diseases. Five members in the mother's family showed respiratory diseases with great diversity in clinical features: her mother was affected by restrictive pneumopathy and emphysema, her grand-mother by asthma and recurrent pneumonia, 2 uncles underwent lung transplantation in the adult age, an aunt was clinically diagnosed having pulmonary fibrosis. All the family members affected by pulmonary diseases and one with no clinical symptoms showed the presence of the mutation 173T. Among the other family members the mutation was found in six subjects for whom no clinical data were available, yet. Our results confirm that heterozygosity for the mutation 173T may cause chronic inflammation of the lung or progressive pulmonary fibrosis. In addition, the possibility to study a large pedigree allowed us to perform a genotype-phenotype correlation indicating a marked phenotypic variability. The diversity in symptoms, age at onset, clinical course, duration of lung disease in the relatives sharing this mutation indicates an incomplete penetrance of the mutation. This might be due to the influence of other genetic factors thus indicating that the phenotype may be complicated by additional components.
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PMID:[Genetic basis in chronic interstitial familial pneumopathy. Familial study of SFTPC]. 1691 Apr 60

The functional role of neutral lipids in the lung is poorly understood. Lysosomal acid lipase (LAL) is a critical enzyme in hydrolysis of cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. Human LAL was over-expressed in a doxycycline-controlled system in mouse respiratory epithelial cells to accelerate intracellular neutral lipid degradation and perturb the surfactant homeostasis in the lung. In this animal system, neutral lipid concentrations of pulmonary surfactant were reduced in bronchoalveolar lavage fluid (BALF) in association with decrease of surfactant protein C (SP-C) gene expression. The size and the number of lamellar bodies in alveolar type II epithelial cells (AT II cells) were significantly reduced accordingly. The number of macrophages required for surfactant recycling in BALF was also significantly reduced. As a result of these combinatory effects, emphysema of the alveolar structure was observed. Taken together, neutral lipid homeostasis is essential for maintenance of lamellar body genesis and the alveolar structure in the lung.
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PMID:Lysosomal acid lipase over-expression disrupts lamellar body genesis and alveolar structure in the lung. 1803 79


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