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)

Chronic bacterial infection and severe, polymorphonuclear neutrophil-dominated endobronchial inflammation are characteristic hallmarks of cystic fibrosis (CF) lung disease. The free radicals generated can be deleterious for structure and function of many proteins. The goal of this study was to investigate the degree of oxidation of pulmonary epithelial lining fluid proteins. BAL fluid (BALF) from 55 children with CF and from 11 patients in a control group were investigated by dot-blot assay for content and by two-dimensional electrophoresis and Western blotting for the pattern of distribution of oxidized proteins. The highest level of oxidative stress, as assessed by the level of protein carbonyls, was found in patients with FEV1 < 80% of predicted or with highly elevated neutrophil counts. Compared to control subjects without lung disease, CF patients with normal lung function and CF patients with a normal neutrophil count in their BALF had significantly higher protein carbonyl levels. The extent of protein oxidation was directly related to the neutrophil granulocyte count and inversely to lung function. Our data support the hypothesis that oxidative damage of pulmonary proteins during chronic and excessive neutrophilic endobronchial inflammation may contribute to the decline of lung function in CF patients.
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PMID:Oxidative changes of bronchoalveolar proteins in cystic fibrosis. 1647 63

Hyperinflammatory host responses to bacterial infection have been postulated to be a key step in the pathogenesis of cystic fibrosis (CF) lung disease. Previous studies have indicated that the CF airway epithelium itself contributes to the hyperinflammation of CF airways via an excessive inflammatory response to bacterial infection. However, it has been controversial whether the hyperinflammation of CF epithelia results from mutations in the CF transmembrane conductance regulator (CFTR) and/or is a consequence of persistent airways infection. Recent studies have demonstrated that intracellular calcium (Ca2+i) signals consequent to activation of apical G protein-coupled receptors (GPCRs) by pro-inflammatory mediators are increased in CF airway epithelia. Because of the relationship between Ca2+i mobilisation and inflammatory responses, the mechanism for the increased Ca2+i signals in CF was investigated and found to result from endoplasmic reticulum (ER) Ca2+ store expansion. The ER Ca2+ store expansion imparts a hyperinflammatory phenotype to chronically infected airway epithelia as a result of the larger Ca2+i mobilisation coupled to an excessive inflammatory response following GPCR activation. The ER expansion is not dependent on ER retention of misfolded DeltaF508 CFTR, but reflects an epithelial response acquired following persistent luminal airway infection. With respect to the mechanism of ER expansion in CF, the current view is that chronic airway epithelial infection triggers an unfolded protein response as a result of the increased flux of newly synthesised inflammatory mediators and defensive factors into the ER compartment. This unfolded protein response is coupled to X-box binding protein 1 (XBP-1) mRNA splicing and transcription of genes associated with the expansion of the protein-folding capacity of the ER (e.g. increases in ER chaperones and ER membranes). These studies have revealed a novel adaptive response in chronically infected airway epithelia, where the increased protein secretory capacity serves to promote epithelial homeostasis by increasing both the secretory and the reparative capacity of the cell. In addition, the increased ER-derived Ca2+i signaling allows the epithelia to amplify its inflammatory responses to infectious agents and exogenous toxicants. This review is devoted to a discussion of these recent findings and their implication for Ca2+i-dependent hyperinflammatory responses in CF airways.
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PMID:The role of intracellular calcium signals in inflammatory responses of polarised cystic fibrosis human airway epithelia. 1662 Jan 34

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

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

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

The aetiology of idiopathic bronchiectasis, a lung disease where chronic inflammation and bacterial infection leads to progressive lung damage, is unknown. A possible role for natural killer cells has been highlighted previously. However, a role for adaptive immunity is suggested by the presence of CD4 and CD8 T cells in diseased lung tissue. Evidence of a human leucocyte antigen (HLA) class II disease association would further implicate a role for adaptive immunity. To establish if there is any HLA association, we analysed HLA-A, HLA-B, HLA-DQA1, HLA-DQB1 and HLA-DRB1 alleles in patients with idiopathic bronchiectasis and controls. Genomic DNA from 92 adults with idiopathic bronchiectasis and 101 healthy controls was analysed by polymerase chain reaction with sequence-specific primers. We found an increase in the prevalence of HLA-DRB1*01 DQA1*01/DQB1*05 genes in idiopathic bronchiectasis; that is, the HLA-DR1, DQ5 haplotype (odds ratio 2.19, 95% confidence interval 1.15-4.16, P = 0.0152) compared with control subjects. The association with HLA-DR1, DQ5 implicates a role for CD4 T cells restricted by these molecules in susceptibility to the progressive lung damage seen in this disease. This may operate either through influencing susceptibility to specific pathogens or to self-reactivity and requires further investigation.
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PMID:Human leucocyte antigen class II association in idiopathic bronchiectasis, a disease of chronic lung infection, implicates a role for adaptive immunity. 1824 Dec 27

Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-beta1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
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PMID:Complex two-gene modulation of lung disease severity in children with cystic fibrosis. 1829 12

Cystic fibrosis (CF) is the most common lethal monogenic disorder in Caucasians, estimated to affect one out of 2500-4000 new-borns. In patients with CF, lack of CF transmembrane conductance regulator (CFTR) Cl(-) channel function leads to progressive pulmonary damage and ultimately to death. Severe and persistent polymorphonuclear neutrophil-dominated endobronchial inflammation and chronic bacterial infection are characteristic hallmarks of CF lung disease. Whether CFTR dysfunction results directly in an increased predisposition to infection and whether inflammation arises independent of infection remains to be established. The loss of functional CFTR in airway epithelial cells promotes depletion and increased oxidation of the airway surface liquid. Activated neutrophils present in airways produce large amounts of proteases and reactive oxygen species (ROS). Together these changes are associated with diminished mucociliary clearance of bacteria, activation of epithelial cell signalling through multiple pathways, and subsequent hyperinflammatory responses in CF airways. The NF-kappaB pathway and Ca(2+) mobilization in airway epithelial cells are believed to be of key importance for control of lung inflammation through regulated production of mediators such as interleukin-8 that participate in recruitment and activation of neutrophils, modulation of apoptosis, and control of epithelial barrier integrity. In this review, the current understanding of the molecular mechanisms by which airway epithelial cells contribute to abnormal lung inflammation in CF, as well as the anti-inflammatory strategies that can be proposed are discussed.
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PMID:Airway epithelial cell inflammatory signalling in cystic fibrosis. 1843 35


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