Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucous (goblet) cell proliferation and hypersecretion of airway mucus are important characteristics of human respiratory disorders, especially chronic bronchitis and cystic fibrosis. These changes in secretory patterns also occur in animals experimentally exposed to chemical irritants such as ozone (O3), sulfur dioxide (SO2), and cigarette smoke. The cellular and molecular mechanisms involved in irritant-induced mucous cell metaplasia (MCM; transformation of airway epithelium, normally devoid of mucous cells, to a secretory epithelium containing numerous mucous cells) are still unclear. We used two experimental models of toxicant-induced MCM in rat airways to study the cellular and molecular changes that occur during the development of this respiratory tract lesion. MCM can be induced in the nasal transitional epithelium of rats by repeated exposure to ambient levels of ozone. In addition, MCM can be induced in the tracheobronchial airways of rats repeatedly exposed to endotoxin, a lipopolysaccharide-protein molecule found in the outer walls of Gram-negative bacteria. The pathogenesis of ozone- or endotoxin-induced MCM has been partially characterized using a variety of morphometric and histochemical techniques. Toxicant-induced changes in the numbers and types of airway epithelial cells have been estimated using morphometric methods designed for estimating the abundance of cell populations. Nasal pulmonary airway tissues are also processed for light microscopy and stained with Alcian Blue (pH 2.5)/Periodic Acid Schiff (AB/PAS) for detection of acidic and neutral mucosubstances (the specific glycoprotein product of mucous cells), respectively, within the tissue. Computerized image analysis is used to quantitate the amount of the stained mucous product within the airway epithelium. To better characterize the molecular and cellular events in the pathogenesis of ozone- or endotoxin-induced MCM in the rat airway epithelium, we are conducting studies to determine when, and in which epithelial cells, the mucin gene is expressed after exposure to the toxicant. In these studies, rats undergo single or repeated exposures to ozone or endotoxin and are then sacrificed immediately or a few days after the end of the exposures. Airway tissues are microdissected from specific regions of the exposed respiratory tract, and changes in mucin core polypeptide mRNA are evaluated by Northern analysis using human and rat mucin cDNA. In future studies using in situ hybridization, we will establish when, and in which epithelial cells, the expression of high molecular weight airway mucin is initiated in response to ozone or endotoxin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. 851 71

During chronic infections in cystic fibrosis, persistence of Pseudomonas aeruginosa is associated with conversion into forms that are associated with conversion into forms that are characterized by a mucoid colony morphology, rough lipopolysaccharide and, paradoxically, decreased systemic virulence. The mutations underlying these changes occur in global regulators, such as alternative sigma factors and their accessory elements.
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PMID:Pseudomonas aeruginosa, mucoidy and the chronic infection phenotype in cystic fibrosis. 852 Aug 88

Cystic fibrosis (CF) patients are hypersusceptible to chronic Pseudomonas aeruginosa lung infections. Cultured human airway epithelial cells expressing the delta F508 allele of the cystic fibrosis transmembrane conductance regulator (CFTR) were defective in uptake of P. aeruginosa compared with cells expressing the wild-type allele. Pseudomonas aeruginosa lipopolysaccharide (LPS)-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. CFTR may contribute to a host-defense mechanism that is important for clearance of P. aeruginosa from the respiratory tract.
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PMID:Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. 853 1

Heat-stable opsonins from sera of cystic fibrosis (CF) patients were investigated for their ability to activate complement. Complement activation by Pseudomonas aeruginosa after opsonization with patient serum was examined in a complement-consumption assay. Absorption of patients' sera with formalin-treated and boiled bacteria removed specific antibodies and the complement activation decreased. We found a positive correlation between serum complement-activation ability and IgG3 antibody levels to lipopolysaccharide (LPS), alginate, and a crude mixture of P. aeruginosa antigens (sonicate) in a group of patients with high levels of anti-Pseudomonas precipitins. In the same group of patients a significant negative correlation was found between complement activation and lung function. Eighteen patients have been followed longitudinally with serum samples covering the pre-infection, the early, and the late stages of chronic infection. Patients with poor lung function showed significantly higher levels of complement-activation capacity. We conclude that patients with high levels of specific IgG3 antibodies are able to induce a high level of complement activation and then develop more aggressive pulmonary tissue damage, probably secondary to local immune complex formation.
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PMID:High levels of complement-activation capacity in sera from patients with cystic fibrosis correlate with high levels of IgG3 antibodies to Pseudomonas aeruginosa antigens and poor lung function. 857 Mar 5

A discerning feature of Pseudomonas aeruginosa strains causing chronic endobronchial infections in cystic fibrosis is their conversion into the mucoid, exopolysaccharide alginate-overproducing phenotype. This morphologically prominent change is caused by mutations which upregulate AlgU (sigma(E)), a novel extreme-stress sigma factor with functional equivalents in gram-negative organisms. In this work, we investigated the role of algU in P. aeruginosa sensitivity to reactive oxygen intermediates, killing by phagocytic cells, and systemic virulence of this bacterium. Inactivation of algU in P. aeruginosa PA01 increased its susceptibility to killing by chemically or enzymatically generated halogenated reactive oxygen intermediates and reduced its survival in bactericidal assays with J774 murine macrophages and human neutrophils. Surprisingly, inactivation of algU caused increased systemic virulence of P. aeruginosa in mouse models of acute infection. The increased lethality of the algU-deficient strain was also observed in the endotoxin-resistant C3H/HeJ mice. Only minor differences between algU+ and algU mutant cells in their sensitivity to human serum were observed, and no differences in their lipopolysaccharide profiles were detected. Intriguingly, while inactivation of algU downregulated five polypeptides it also upregulated the expression of seven polypeptides as determined by two-dimensional gel analyses, suggesting that algU plays both a positive and a negative role in gene expression in P. aeruginosa. While the observation that algU inactivation increases systemic virulence in P. aeruginosa requires further explanation, this phenomenon contrasts with the apparent selection for strains with upregulated AlgU during colonization of the cystic fibrosis lung and suggests opposing roles for this system in chronic and acute infections.
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PMID:Virulence properties of Pseudomonas aeruginosa lacking the extreme-stress sigma factor AlgU (sigmaE). 869 7

Pseudomonas aeruginosa isolates recovered from chronically colonized patients with cystic fibrosis (CF) are phenotypically different from those collected from other patients or from the environment. To assess whether alterations in motility, mucoidy, and serum susceptibility represented an adaptation to chronic infection or replacement by a new strain, sequential P. aeruginosa isolates of known phenotype collected from 20 CF patients were typed by random amplified polymorphic DNA (RAPD) analysis. A total of 35 RAPD strain types were found among 385 isolates from 20 patients, and only two patients had P. aeruginosa strains of the same RAPD fingerprint. Eight strain pairs representative of the first eight RAPD types were also analyzed by SpeI macrorestriction followed by pulsed-field gel electrophoresis (PFGE); the strain types found by both fingerprinting techniques correlated exactly. In 11 of 20 patients, the RAPD types of serial P. aeruginosa isolates remained stable despite alterations in isolate motility, colonial morphology, and lipopolysaccharide phenotype. However, in isolates collected from one CF patient, a single band change in RAPD fingerprint and CeuI PFGE profile correlated with the appearance of an RpoN mutant phenotype, suggesting that the altered phenotype may have been due to a stable genomic rearrangement. Secretion of mucoid exopolysaccharide, loss of expression of RpoN-dependent surface factors, and acquisition of a serum-susceptible phenotype in P. aeruginosa appear to evolve during chronic colonization in CF patients from specific adaptation to infection rather than from acquisition of new bacterial strains.
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PMID:Random amplified polymorphic DNA typing of Pseudomonas aeruginosa isolates recovered from patients with cystic fibrosis. 872 89

Cystic fibrosis (CF) patients develop progressive cytokine-mediated inflammatory lung disease, with abundant production of thick, tenacious, protease- and oxidant-rich purulent airway secretions that are difficult to clear even with physiotherapy. In the search for a potential treatment, we have tested tyloxapol, an alkylaryl polyether alcohol polymer detergent previously used as a mucolytic agent in adult chronic bronchitis. Tyloxapol inhibits activation of the transcription factor nuclear factor-kappa B (NK-kappa B), reduces resting secretion of the cytokine interleukin-8 (IL-8) in cultured human monocytes, and inhibits lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the eiconsanoids thromboxane A2 and leukotriene B4 (LTB4). We have previously shown that tyloxapol is a potent antioxidant for hydroxyl radicals ( OH). Tyloxapol (0.05 to 0.1% wt/vol) effectively scavenges the oxidant hypochlorous acid (HOCl; 1 to 7.5 mM) in vitro, and protects from HOCl-mediated lung injury in rats. Tyloxapol also reduces the viscosity of CF sputum (from 463 +/- 133 to 128 +/- 52 centipoise). We conclude that tyloxapol is potentially useful as a new antiinflammatory therapy for CF lung disease, and could possibly promote clearance of secretions in the CF airway.
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PMID:Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum. 881 Jun 19

Patients with cystic fibrosis (CF) have a pronounced hypersusceptibility (80 to 90%) to Pseudomonas aeruginosa infection. We hypothesized that airway epithelial cell ingestion of bacteria followed by cellular desquamation may protect the lung from infection, and epithelial cells expressing mutant forms of the cystic fibrosis transmembrane conductance regulator (CFTR) may be defective in this function. We found that transformed human airway epithelial cells homozygous for the delta F508 allele of CFTR were significantly defective in uptake of P. aeruginosa compared with the same cell line complemented with the wild-type allele of CFTR. Partial membrane expression of the delta F508 CFTR protein occurs in cells grown at 26 degrees C, and under these conditions uptake of P. aeruginosa occurred at levels comparable to cells with a wild-type allele of CFTR. Epithelial cell ingestion assays using isogenic bacterial strains differing in lipopolysaccharide (LPS) phenotype, along with inhibition studies, identified the LPS-core oligosaccharide as the bacterial ligand for epithelial cell invasion. Inhibition of epithelial cell ingestion of P. aeruginosa in a neonatal mouse lung infection model led to increased levels of bacteria in the lungs 24 and 48 h after infection. Defective epithelial cell internalization of P. aeruginosa may be a critical factor in hypersusceptibility of CF patients to chronic lung infections.
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PMID:How mutant CFTR may contribute to Pseudomonas aeruginosa infection in cystic fibrosis. 887 38

Pseudomonas aeruginosa is a common respiratory tract pathogen that causes serious infections in patients with cystic fibrosis. A number of putative virulence factors have been characterized in several laboratories, and some have been implicated in human infections, based on criteria such as the phenotype of isolates from infected patients, an immune response to a particular antigenic factor, and the effect of a virulence factor on infectivity in an animal model. We have developed a series of genetic tools to study the selective regulation of expression of P. aeruginosa genes during interactions of the pathogen with host tissues. These tools are based on direct enrichment of bacteria, when a particular promoter is induced or repressed. We have found that interaction of bacteria with mucus from patients with cystic fibrosis results in marked induction of expression of several genes, including one that encodes a lipopolysaccharide biosynthetic enzyme, a gene for a protein responsible for uptake of the ferric pyochelin siderophore, and a new gene homologous with a class of iron-responsive repressors. The tools described here are useful for identification of induced or repressed genes in various animal models of infection or in controlled laboratory conditions that mimic natural infections of humans. Such genes might not be detectable when bacteria are cultured in laboratory conditions, and these tools are therefore useful for general probing of a bacterial genome for genes regulated during different stages of infection.
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PMID:Differential gene expression by Pseudomonas aeruginosa during interaction with respiratory mucus. 887 39

The frequency of isolation of Burkholderia cepacia from the sputum of cystic fibrosis (CF) patients is increasing. Using the human A549 lung epithelial cell line, we have investigated the ability of B. cepacia exoproducts to stimulate interleukin-8 (IL-8) release. Cell-free supernatants from a panel of CF clinical, non-CF clinical, and nonclinical B. cepacia isolates were found to stimulate IL-8 release, with levels ranging from 11.8 +/- 2.8 to 80.0 +/- 3.5 ng/ml. A similar pattern was seen at the level of the IL-8 mRNA. The bioactivity of the IL-8 was confirmed by examining its effect on the intracellular free calcium in neutrophils and inhibition by a neutralizing anti-IL-8 antibody. B. cepacia lipopolysaccharide, which was able to stimulate IL-8 release from monocytes, did not release IL-8 from the A549 cells. Furthermore, the stimulating ability of the bacterial cell-free supernatant was not diminished by polymyxin B, was markedly reduced by boiling, and appeared unrelated to N-acylhomoserine lactones. The ability of B. cepacia to elicit IL-8 release from epithelial cells may be important in the pathology of CF.
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PMID:Induction of biologically active interleukin-8 from lung epithelial cells by Burkholderia (Pseudomonas) cepacia products. 900 21


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