Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004623 (bacterial infection)
 15,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystic fibrosis (CF) is the most common genetic disease among Caucasians and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF affects multiple organs but lung disease is the major determinant for morbidity and mortality. Many studies have focussed on the correlation between CFTR genotype and severity of disease. Since patients with identical CFTR mutations often show considerable variability in disease progression, genes other than CFTR are thought to have the potential to modify the course of lung disease in CF patients. Therefore, identification of CF-modifying genes has become the goal of several studies over the last 15 years. Pharmaceutical approaches for CF lung disease have been developed regardless of the underlying genetic defect and in general target symptoms such as airway obstruction and treatment of bacterial infection. Analysing the pathophysiological processes of modifiers may lead to the discovery of pathways involved in CF pathophysiology and possibly to the design of new therapeutics. The purpose of this review is not only to list potential CFTR modifier genes, but also to discuss new therapeutic strategies that could be derived from knowledge of these CF modifiers.
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PMID:Disease modifying genes in cystic fibrosis: therapeutic option or one-way road? 1703 96

Increased serum levels of the S100A8 (MRP-8) protein have been reported in inflammatory conditions including bacterial infection, arthritis, and cystic fibrosis (CF). This protein is expressed constitutively with S100A9 (MRP-14) in neutrophils and is regulated by inflammatory stimulants. It has been hypothesized that increased inflammatory response to persistent bacterial infection is a major feature of CF lung disease. Therefore, the authors wished to determine the involvement of these two proteins in the innate defense response of the bronchial epithelium to lipopolysaccharide (LPS). Human bronchial epithelial cells (16HBE14o-) and primary bronchial epithelial cells (NHBE) were grown at air-liquid interface (ALI) and stimulated for up to 96 hours with LPS from Pseudomonas aeruginosa. The 16HBE14o- cells responded to LPS with a 2.9-fold increase in S100A8 mRNA production after 12 hours. S100A9 mRNA production was increased by 1.8-fold after 12 hours and 2.9-fold after 24 hours. It was also found that the S100A8 and S100A9 proteins were increased in the secretions of the 16HBE14o- and NHBE cells after LPS stimulation. This finding suggests that S100A8 and S100A9 are involved in the innate defense of the bronchial epithelium.
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PMID:Up-regulation of S100A8 and S100A9 protein in bronchial epithelial cells by lipopolysaccharide. 1709 Apr 75

Chronic Pseudomonas aeruginosa infection, as occurs in cystic fibrosis, is associated with decreased surfactant phospholipid levels. To investigate mechanisms, we measured synthesis of dipalmitoylphosphatidylcholine (DPPC), the major surfactant phospholipid. Mice received an agarose bead slurry alone, or were infected with beads containing a clinical mucoid isolate of P. aeruginosa. Bacterial infection after 3 days resulted in a approximately 50% reduction in surfactant DPPC content versus control. These changes in surfactant were associated with co-ordinate reductions in mRNAs and immunoreactive levels for CTP: phosphocholine cytidylyltransferase (CCTalpha), the rate-regulatory enzyme required for DPPC synthesis. P. aeruginosa infection of murine lung epithelia decreased CCTalpha gene transcription without altering mRNA stability and by a mechanism other than release of a soluble extracellular inhibitor. Promoter deletional analysis revealed that P. aeruginosa activates a negative response element from -1019 to -799 bp of the CCTalpha proximal 5'-flanking region. Exposure of cells to a P. aeruginosa mutant strain producing alginate reduced CCTalpha promoter activity, whereas these effects were not observed in strains defective in alginate synthesis. Murine type II cells isolated from P. aeruginosa-infected CCTalpha promoter-beta-galactosidase transgenic mice exhibited significantly reduced CCT and beta-galactosidase enzyme activities versus control. Thus, a mucoid P. aeruginosa strain reduces mRNA synthesis of a key biosynthetic enzyme thereby decreasing levels of surfactant.
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PMID:Chronic Pseudomonas aeruginosa infection reduces surfactant levels by inhibiting its biosynthesis. 1716 34

Cystic fibrosis (CF) lung disease reflects the failure of airways defense against chronic bacterial infection. Studies of CF cultures, transgenic mice, and CF patients suggest that the initiating event in CF airways disease pathogenesis is reduced airway surface liquid (ASL) volume, i.e., dehydration. CF ASL volume regulation depends on a single extracellular signaling system, ATP, which renders CF airways more vulnerable to disease-causing insults (e.g., viruses) than are normal airways, which regulate ASL volume by dual ATP and adenosine signaling pathways. Clinical studies have explored the hypothesis that treating the dehydration of CF airways will be therapeutically beneficial. Inhaled hypertonic saline osmotically draws water onto airway surfaces, improves mucus clearance and pulmonary function, and reduces acute exacerbations in CF patients. Thus, rehydration therapies may slow the progression of CF lung disease in patients with established bacterial infection and may prevent the onset of CF lung disease if initiated early in life.
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PMID:Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. 1721 30

Cystic fibrosis (CF) lung disease reflects persistent bacterial infection of airway lumens. Several hypotheses have been advanced to link mutations in the CFTR gene to the failure of the CF lung to defend itself against bacterial infection. Amongst the most productive hypotheses at present is the ''low airway surface liquid (ASL) volume'' or ''dehydration'' hypothesis. This hypothesis predicts that airway surface dehydration produces the mucus adhesion, inflammation, and bacterial biofilm formation characteristic of CF. Clinical trials of inhaled hypertonic saline have demonstrated therapeutic benefit of manoeuvres designed to rehydrate CF airway surfaces.
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PMID:Evidence for airway surface dehydration as the initiating event in CF airway disease. 1722 64

In the lungs, the first line of defence against bacterial infection is the thin layer of airway surface liquid (ASL) lining the airway surface. The superficial airway epithelium exhibits complex regulatory pathways that blend ion transport to adjust ASL volume to maintain proper mucociliary clearance (MCC). We hypothesized that stresses generated by airflow and transmural pressures during breathing govern ASL volume by regulating the rate of epithelial ATP release. Luminal ATP, via interactions with apical membrane P2-purinoceptors, regulates the balance of active ion secretion versus absorption to maintain ASL volume at optimal levels for MCC. In this study we tested the hypothesis that cyclic compressive stress (CCS), mimicking normal tidal breathing, regulates ASL volume in airway epithelia. Polarized tracheobronchial epithelial cultures from normal and cystic fibrosis (CF) subjects responded to a range of CCS by increasing the rate of ATP release. In normal airway epithelia, the CCS-induced increase in ASL ATP concentration was sufficient to induce purinoceptor-mediated increases in ASL height and MCC, via inhibition of epithelial Na(+)-channel-mediated Na(+) absorption and stimulation of Cl(-) secretion through CFTR and the Ca(2+)-activated chloride channels. In contrast, static, non-oscillatory stress did not stimulate ATP release, ion transport or MCC, emphasizing the importance of rhythmic mechanical stress for airway defence. In CF airway cultures, which exhibit basal ASL depletion, CCS was partially effective, producing less ASL volume secretion than in normal cultures, but a level sufficient to restore MCC. The present data suggest that CCS may (1) regulate ASL volume in the normal lung and (2) improve clearance in the lungs of CF patients, potentially explaining the beneficial role of exercise in lung defence.
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PMID:Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia. 1736 80

Cystic fibrosis (CF) is characterized by a solute transport defect in epithelial tissues. In the lungs, this defect culminates in the dehydration of the airway surface and mucus accumulation, ultimately leading to chronic bacterial infection. To date, the current therapeutic approaches used to treat CF primarily focus on the secondary manifestations of the disease (e.g. bacterial infection, viscous mucus). However, new therapeutic approaches are targeting the underlying ion transport defect in cystic fibrosis, with the aim of restoring the function of the cystic fibrosis transmembrane conductance regulator, stimulating alternative chloride channels, inhibiting sodium absorption, and utilizing hyperosmotic agents to rehydrate the airway surface. Although still in the development phase, these approaches, used by themselves or in combination, show great promise in the treatment of CF.
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PMID:The epithelium as a target for therapy in cystic fibrosis. 1747 61

Bronchiectasis is characterised by permanent dilatation of the bronchi that arises from chronic inflammation predominantly caused by bacterial infection. This condition remains a major cause of excess respiratory morbidity and treatment is generally only partly successful. There is an urgent need for improved anti-inflammatory medication to treat bronchiectasis. Two potentially useful therapies are inhaled corticosteroids (ICS) and macrolides. The clinical trials that have been performed in bronchiectasis with these two medications can be considered to be preliminary data. This article reviews the anti-inflammatory properties, clinical efficacy and adverse effects of ICS and macrolides.ICS have a large number of potent anti-inflammatory properties. ICS remain the first-line treatment in asthma, reduce exacerbations in chronic obstructive pulmonary disease, and may improve lung function and symptoms in cystic fibrosis (CF). Four small clinical trials have assessed the effect of high-dose ICS on bronchiectasis. The main reported effect of these trials was a reduction in sputum volume and this may be a marker of decreased airway inflammation. Other possible benefits included decreased cough and sputum inflammatory cells/biomarkers. ICS have a relatively high prevalence of local adverse effects, and may be associated with ocular complications and osteoporosis. These adverse effects can be minimised by prescribing low doses of the medication. Macrolides have both antibacterial and immunomodulatory properties. Macrolides have less marked immunosuppressive properties than corticosteroids, and effects include decreasing mucous production, inhibiting virulence factors and biofilm formation of Pseudomonas aeruginosa, decreasing leukocyte numbers and altering inflammatory mediator release. Macrolides have been shown to be extremely effective in the treatment of diffuse panbronchiolitis, improve lung function and symptoms in asthma and CF, and reduce nasal polyps and secretions in sinusitis. Five small clinical trials have assessed the effect of macrolides on bronchiectasis. Reported benefits include reduced sputum volume, improved lung function and better symptom control. Macrolides are generally well tolerated, although they do have a number of drug interactions. There are concerns about the development of resistance, especially to non-tuberculous mycobacteria, with prolonged macrolide use. The evidence available suggests that both medications have a role in the management of bronchiectasis. More definitive trials of ICS and macrolides in bronchiectasis will clarify the likely benefit of these therapies.
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PMID:Is there a role for inhaled corticosteroids and macrolide therapy in bronchiectasis? 1748 42

Cystic fibrosis (CF) lung disease involves chronic bacterial infection of retained airway secretions (mucus). Recent data suggest that CF lung disease pathogenesis reflects the vulnerability of airway surfaces to dehydration and collapse of mucus clearance. This predisposition is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in (i) the absence of CFTR-mediated Cl- secretion and regulation of epithelial Na+ channel (ENaC) function; and (ii) the sole dependence on extracellular ATP to rebalance these ion transport processes through P2 purinoceptor signaling. Recent clinical studies indicate that inhalation of hypertonic saline osmotically draws sufficient water onto CF airway surfaces to provide clinical benefit.
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PMID:Cystic fibrosis: a disease of vulnerability to airway surface dehydration. 1752 5

Recurrent Gram-negative bacterial infection is a significant cause of death in patients with bronchiectasis and severe chronic obstructive pulmonary disease (COPD). Nebulized colistin in cystic fibrosis has shown maintenance of pulmonary function and improved symptom scores. We prospectively followed 18 patients with chronic bronchial sepsis treated with nebulized colistin 30 mg daily. Mean decline in forced expiratory volume in 1 s was significantly slower following commencement of inhaled colistin (44 mL/year vs 104 mL/year, P = 0.035). Mean decline in forced vital capacity was also significantly slower following commencement of colistin (48 mL/year vs 110 mL/year, P = 0.033). Patient-reported quality of life improved following commencement of colistin (3.6 vs 6.2, P = 0.001). No patient had isolates resistant to colistin. No side-effects were reported by patients in the cohort. Use of inhaled colistin in the treatment of bronchiectasis and severe (COPD) in patients with recurrent Gram-negative infections is safe. Inhaled colistin may improve quality of life and slow decline in forced expiratory volume in 1 s and forced vital capacity.
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PMID:Effect of long-term nebulized colistin on lung function and quality of life in patients with chronic bronchial sepsis. 1754 27


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