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: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystic fibrosis (CF) is the most common severe, autosomal recessive disease in Caucasians. The main clinical symptoms are all related to exocrine gland disturbances and include obstructive lung disease, pancreatic insufficiency and increased sweat electrolytes. In the present investigation fibroblasts from CF homozygotes were studied by X-ray microanalysis and were shown to have an increased calcium and a decreased sodium content, compared with fibroblasts from controls. The calcium increase was not specific for CF, since it was also found in fibroblasts from trisomy patients. The calcium abnormality could be corrected without any effect on the sodium level by treatment of CF cells with medium conditioned by normal cells. When normal cells were treated with medium conditioned by CF cells, the intracellular sodium level decreased without changes in the calcium level. Acid hydrolases were quantitatively increased in serum from CF patients but no qualitative differences, neither in thermal stability nor in isoelectric focusing patterns were found. Neither was any defect observed in the recognition marker of the hydrolases released from CF fibroblasts. CF homozygotes and heterozygotes had increased concentrations of lactate and electrolytes and increased activities of ribonuclease in their saliva and urine. The salivary concentration of protein was also elevated. When healthy controls were submitted to intensive maximal (anaerobic) exercise on a bicycle ergometer their salivary contents of lactate, ribonuclease, protein and electrolytes increased. Their saliva thus became more like that in CF patients. Indications of abnormal handling of a load dose of sucrose were found in both homozygotes and heterozygotes. Greater increases in the salivary concentrations of both glucose and lactate, but also a more rapid clearance of these metabolites were noted after the sucrose intake. Ingestion of sucrose also caused a normalization (decrease) of the salivary electrolyte content in homozygotes and heterozygotes. Evidence was thus produced to indicate a disturbance in the metabolism of carbohydrates and energy in cystic fibrosis, and it is speculated that such a disturbance might be of importance for the pathogenesis of this disease.
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PMID:Cystic fibrosis. In vitro and in vivo studies on the biochemical background to the pathogenesis. 658 81

Inhalation of fibrogenic particles causes injury to the bronchiolar-alveolar epithelium. Consequently, there is a rapid proliferative response as the epithelium recovers and interstitial mesenchymal cells divide and produce connective tissue. In our model of brief (5-hr) exposure to chrysotile asbestos (approximately 1000 fibers/cc) in rats and mice, these events result in focal scarring at the bronchiolar-alveolar duct junctions in a histopathologic pattern identical to that seen in asbestos-exposed individuals. After 3 consecutive days of exposure, these lesions persist for at least 6 months postexposure. We postulate that cell proliferation and production of extracellular matrix is mediated in large part by three peptide growth factors, transforming growth factors alpha and beta (TGF-alpha and -beta), and platelet-derived growth factor (PDGF) A- and B-chains. To test this hypothesis in part, we have asked whether the genes that code for these growth factor proteins are activated at sites of asbestos-induced lung injury. If these genes were not activated, it would be reasonable to suspect that other potent growth factors and cytokines released during lung injury could be the primary mediators of fibroproliferative lung disease. In the studies reported here, we show, by in situ hybridization (ISH) and immunohistochemistry, that the four genes and their concomitant proteins are expressed within 24 hr in the bronchiolar-alveolar epithelium and underlying mesenchymal cells. RNase protection assay and ISH showed that the PDGF gene was upregulated during the first 5 hr of exposure and all the gene products remained above control levels for at least 2 weeks postexposure. TGF-alpha is a potent mitogen for epithelial cells, whereas the PDGF isoforms are potent growth factors for mesenchymal cells. TGF-beta retards fibroblast growth but stimulates extracellular matrix synthesis. Further studies using gene knockouts, appropriate antibodies, or antisense technology will be necessary to prove whether any of the growth factors are playing a significant role in fibrogenic lung disease. In addition, we have carried out a series of studies using type II alveolar epithelial cells purified from adult mouse lungs and maintained for up to 8 weeks in serum-free culture. These cells exhibit high transepithelial resistance values and they release TGF-beta 1 and -beta 2. This cell type also has been cultured from TGF-alpha knockout mice, resulting in monolayers with increased transepithelial resistance. This combination of studies in vivo and in vitro will allow us to pursue the mechanisms through which growth factors mediate lung fibrosis.
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PMID:Analyzing the genes and peptide growth factors expressed in lung cells in vivo consequent to asbestos exposure and in vitro. 940 Jul 18

Bacterial infection of the lung is associated with mucin overproduction. In partial explanation of this phenomenon, we recently reported that supernatant from the Gram-negative organism Pseudomonas (P.) aeruginosa contained an activity that upregulated transcription of the MUC 2 mucin gene [J.-D. Li, A. Dohrman, M. Gallup, S. Miyata, J. Gum, Y. Kim, J. Nadel, A. Prince, C. Basbaum, Transcriptional activation of mucin by P. aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease, Proc. Natl. Acad. Sci. U.S.A., 94 (1997) 967-972]. The purpose of the present study was to determine whether mucin genes other than MUC 2 are so regulated and whether Gram-positive organisms also contain mucin stimulatory activity. Results from in situ hybridization and RNase protection assays showed that P. aeruginosa upregulates MUC 5AC as well as MUC 2 in both bronchial explants and cultured airway epithelial cells. The upregulation of both genes by P. aeruginosa can be mimicked by lipopolysaccharide (LPS) and can be blocked by the tyrosine kinase inhibitor genistein. In addition, both genes are upregulated by a variety of Gram-positive as well as Gram-negative organisms showing the same rank order of potency. These data indicate the existence of a general mechanism by which epithelial cells respond to the presence of bacteria by increasing mucin synthesis.
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PMID:Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. 963 Jun 59

Pseudomonas aeruginosa, an opportunistic human pathogen, causes acute pneumonia in patients with hospital-acquired infections and is commonly associated with chronic lung disease in individuals with cystic fibrosis (CF). Evidence suggests that the pathophysiological effects of P. aeruginosa are mediated in part by virulence factors secreted by the bacterium. Among these factors is pyocyanin, a redox active compound that increases intracellular oxidant stress. We find that pyocyanin increases release of interleukin-8 (IL-8) by both normal and CF airway epithelial cell lines and by primary airway epithelial cells. Moreover, pyocyanin synergizes with the inflammatory cytokines tumor necrosis factor alpha and IL-1alpha. RNase protection assays indicate that increased IL-8 release is accompanied by increased levels of IL-8 mRNA. The antioxidant n-acetyl cysteine, general inhibitors of protein tyrosine kinases, and specific inhibitors of mitogen-activated protein kinases diminish pyocyanin-dependent increases in IL-8 release. Conversely, inhibitors of protein kinases C (PKC) and PKA have no effect. In contrast to its effects on IL-8 expression, pyocyanin inhibits cytokine-dependent expression of the monocyte/macrophage/T-cell chemokine RANTES. Increased release of IL-8, a potent neutrophil chemoattractant, in response to pyocyanin could contribute to the marked infiltration of neutrophils and subsequent neutrophil-mediated tissue damage that are observed in Pseudomonas-associated lung disease.
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PMID:Pseudomonas pyocyanin increases interleukin-8 expression by human airway epithelial cells. 982 54

Acute hyperoxic lung injury remains a major factor in the development of chronic lung disease in neonates. A critical step in the repair of acute lung injury is the proliferation of type II alveolar epithelial cells. Type II cell proliferation is stimulated by keratinocyte growth factor (KGF), an epithelial cell-specific mitogen. We sought to investigate KGF mRNA expression in relation to type II cell proliferation during hyperoxic lung injury. We studied a previously described newborn (NB) rabbit model of acute and chronic hyperoxic injury [C. T. D'Angio, J. N. Finkelstein, M. B. LoMonaco, A. Paxhia, S. A. Wright, R. B. Baggs, R. H. Notter, and R. M. Ryan. Am. J. Physiol. 272 (Lung Cell. Mol. Physiol. 16): L720-L730, 1997]. NB rabbits were placed in 100% O2 for 9 days and then recovered in 60% O2. RT-PCR was used to synthesize and amplify a 267-bp fragment of rabbit KGF cDNA from whole lung RNA. KGF mRNA expression was analyzed by ribonuclease protection assay, and mRNA abundance was quantified by phosphorimaging. Proliferating cell nuclear antigen immunohistochemistry was used on lung sections to identify proliferating cells. The rabbit partial cDNA sequenced was >95% homologous to human cDNA, and all amino acids were conserved. Whole lung KGF mRNA expression was increased 12-fold after 6 days of hyperoxia compared with control lungs, and remained increased throughout the 100% O2 exposure period. Proliferating cell nuclear antigen immunohistochemistry showed an increase in type II cell proliferation after 8-12 days of hyperoxia. NB rabbits exposed to hyperoxic injury exhibit increased whole lung KGF mRNA expression preceding type II cell proliferation. KGF may be an important mitogen in the regulation of alveolar epithelial repair after hyperoxic lung injury.
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PMID:Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung. 988 62

Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pulmonary disease. In the current study, Western analysis, immunohistochemistry, and ribonuclease protection assays were used to determine whether TNF-alpha regulates the expression of these TNFR-associated proteins in lung cells. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflammation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born infants. Immunohistochemical staining of human neonatal lung tissue demonstrated increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a role in human lung disease.
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PMID:Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2. 1065 35

The bronchiolar-alveolar epithelium (BAE) is a primary target site for inhaled agents that cause lung injury. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of interstitial pulmonary fibrosis (IPF). A number of peptide growth factors (GF) have been postulated to be essential in the pathogenesis of IPF. We demonstrate here that primary populations of mouse BAE and mesenchymal cells, maintained in culture, synthesize four potent GF. These are platelet-derived growth factor isoforms (PDGF) A and B, transforming growth factor beta-1 (TGF-beta(1)), and tumor necrosis factor alpha (TNF-alpha). A mouse lung epithelial cell isolation technique pioneered in this laboratory has been used to purify the BAE cells to greater than 85% (80 +/- 5.6% alveolar type II and 9 +/- 2.3% Clara cells) in culture. Northern analysis, RNase protection assay, and immunocytochemistry (ICC) were used to establish mRNA and protein expression of the GF over time in the cultured BAE and mesenchymal cells. We show for the first time in these primary mouse lung cells that treatment of both cell types with TNF-alpha upregulates expression of TGF-beta(1). The four GF are produced by both epithelial and mesenchymal cells but with different temporal patterns. TGF-beta(1) is expressed constitutively by BAE and mesenchymal cells, whereas TNF-alpha expression wanes over time. The findings by ICC were consistent with levels of mRNA expression in both cell types. As genetically defined and altered mouse strains are becoming increasingly valuable for modeling lung disease, studying the gene expression patterns of target cells from these animals in vitro would be useful in sorting out the complex responses by individual cell types of the lung and the interactions among the multitude of mediators that are released during lung cell injury.
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PMID:TNF-alpha, PDGF, and TGF-beta(1) expression by primary mouse bronchiolar-alveolar epithelial and mesenchymal cells: tnf-alpha induces TGF-beta(1). 1150 94

Chloride transport is critical to many functions of the lung. Molecular defects in the best-known chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), lead to impaired function of airway defensins, hydration of airway surface fluid, and mucociliary clearance leading to chronic lung disease, and premature death, but do not cause defects in lung development. We examined the expression of one member of the ClC family of volume- and voltage-regulated channels using the ribonuclease protection assay and Western blot analysis in rats. ClC-5 mRNA and protein are most strongly expressed in the fetal lung, and expression is maintained although downregulated postnatally. In addition, using immunocytochemistry, we find that ClC-5 is predominantly expressed along the luminal surface of the airway epithelium, suggesting that ClC-5 may participate in lung chloride secretion. Identifying candidate genes for critical ion transport functions is essential for understanding normal lung morphogenesis and the pathophysiology of several lung diseases. In addition, the manipulation of non-CFTR chloride channels may provide a viable approach for treating cystic fibrosis lung disease.
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PMID:ClC-5: ontogeny of an alternative chloride channel in respiratory epithelia. 1183 44

Fibroblast apoptosis is crucial to the resolution of fibrosis. However, the mechanisms by which these cells undergo apoptosis are not well known. Because interleukin (IL)-6 and IL-11 may alter repair and remodeling processes, we hypothesized that they may play a role in idiopathic pulmonary fibrosis (IPF). We investigated the effects of these cytokines on Fas-induced apoptosis using primary lung fibroblasts from three patients with IPF (IPF-Fb) and three subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas-induced apoptosis compared with normal-Fb (P < 0.01). Using RNase protection assays, we showed that IL-6 enhanced Fas-induced apoptosis and expression of Bax in normal-Fb, but inhibited apoptosis and induced expression of Bcl-2 in IPF-Fb. Densitometry of Western blots revealed a Bcl-2/Bax ratio 0.15 +/- 0.01 in normal-Fb compared with 12.05 +/- 1.0 in IPF-Fb. Upregulation of Bcl-2 in normal-Fb and Bax in IPF-Fb were both STAT-3-dependent. Inhibition of extracellular signal-regulated kinase had no effect in normal-Fb, but reversed the antiapoptotic effect of IL-6 in IPF-Fb. IL-11 inhibited Fas-induced apoptosis and increased Bcl-2 expression in both normal-Fb and IPF-Fb. These results suggest that altered IL-6 signaling in IPF-Fb may enhance the resistance of these cells to apoptosis and contribute to a profibrotic effect of IL-6 in IPF.
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PMID:Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. 1271 76

Isocyanates are a common cause of occupational lung disease. Hexamethylene diisocyanate (HDI), a component of polyurethane spray paints, can induce respiratory symptoms, inflammation, lung function impairment, and isocyanate asthma. The predominant form of HDI in polyurethane paints is a nonvolatile polyisocyanate known as HDI biuret trimer (HDI-BT). Exposure of mice to aerosolized HDI-BT results in pathological effects, including pulmonary edema, lung inflammation, cellular proliferation, and fibrotic lesions, which occur with distinct time courses following exposure. To identify genes that mediate lung pathology in the distinct temporal phases after exposure, gene expression profiles in HDI-BT-exposed C57BL/6J mouse lungs were analyzed. RNase protection assay (RPA) of genes involved in apoptosis, cell survival, and inflammation revealed increased expression of IkappaBalpha, Fas, Bcl-X(L), TNFalpha, KC, MIP-2, IL-6, and GM-CSF following HDI-BT exposure. Microarray analysis of approximately 10000 genes was performed on lung RNA collected from mice 6, 18, and 90 h after HDI-BT exposure and from unexposed mice. Classes of genes whose expression was increased 6 h after exposure included those involved in stress responses (particularly oxidative stress and thiol redox balance), growth arrest, apoptosis, signal transduction, and inflammation. Types of genes whose expression was increased at 18 h included proteinases, anti-proteinases, cytoskeletal molecules, and inflammatory mediators. Transcripts increased at 90 h included extracellular matrix components, transcription factors, inflammatory mediators, and cell cycle regulators. This characterization of the gene expression profile in lungs exposed to HDI-BT will provide a basis for investigating injury and repair pathways that are operative during isocyanate-induced lung disease.
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PMID:Gene expression profiling in mouse lung following polymeric hexamethylene diisocyanate exposure. 1588 64


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