Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa is less cytotoxic than that from Escherichia coli. But P. aeruginosa induces a prominent sustained lung inflammation as in cystic fibrosis and diffuse panbronchiolotis. The present study examined the potential for several LPSs obtained from E. coli and P. aeruginosa to release neutrophil chemotactic activity (NCA) from lung cells. LPSs differently stimulated A549 cells, BEAS-2B cells, and lung fibroblasts to release NCA [P. aeruginosa > E. coli 0127:B8 (Difco) > E. coli 055:B5 (Sigma) > E. coli 026:B6 (Sigma)]. E. coli 0127:B8 (Sigma) and 0111:B4 (Sigma) did not stimulate these cells. NCA was chemotactic by checkerboard analysis. Molecular-sieve column chromatography revealed three chemotactic peaks. The release of NCA was inhibited by cycloheximide and lipoxygenase inhibitors. Experiments with blocking antibodies suggested that much of the NCA was secondary to the release of interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF). Thus we examined the concentrations of IL-8 and G-CSF and found that the potency of the various LPSs to stimulate NCA closely paralleled the potency in releasing IL-8 and G-CSF. But a difference among LPSs to stimulate A549 cells was observed. Finally, the release of IL-6 showed similar results. These data suggest that P. aeruginosa LPS may stimulate lung cells to release more NCA than E. coli LPSs, leading to sustained lung inflammation.
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PMID:The potential of various lipopolysaccharides to release IL-8 and G-CSF. 1074 42

Pseudomonas aeruginosa infection of cystic fibrosis patients causes lung damage that is substantially orchestrated by cytokines. In this study, multi-gene probe analysis was used to characterize the ability of the P. aeruginosa mitogen, exoenzyme S, to induce proinflammatory and immunoregulatory cytokines and chemokines. Exoenzyme S strongly induced transcription of proinflammatory cytokines and chemokines (tumor necrosis factor alpha, interleukin-1alpha [IL-1alpha], IL-1beta, IL-6, IL-8, MIP-1alpha, MIP-1beta, MCP-1, RANTES, and I-309), modest transcription of immunoregulatory cytokines (IL-10 and IL-12p40), and weak transcription of Th1 cytokines (IL-2 and gamma interferon). The response occurred early and subsided without evolving over time. These data suggest that cells responding to exoenzyme S would rapidly express proinflammatory cytokines and chemokines that may contribute to pulmonary inflammation in cystic fibrosis.
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PMID:Pseudomonas aeruginosa exoenzyme S induces transcriptional expression of proinflammatory cytokines and chemokines. 1089 95

Exacerbated inflammation is now recognized as an important component of cystic fibrosis (CF) airway disease. Whether inflammation is part of the basic defect in CF or a response to persistent infection remains controversial. We addressed this question using human fetal tracheal grafts in severe combined immunodeficient mice. This model yields histologically mature, and most importantly, naive CF and non-CF surrogate airways. Significant inflammatory imbalance was found in naive CF airway grafts, including a highly increased intraluminal interleukin 8 content (CF: 10.1 +/- 2.2 ng/ml; non-CF: 1.2 +/- 0.6 ng/ml; P < 0.05) and consistent accumulation of leukocytes in the subepithelial region (P < 0.001). CF airway grafts were not histologically affected until challenged with Pseudomonas aeruginosa, which provoked: (1) early (before 3 h) and massive leukocyte transepithelial migration, (2) intense epithelial exfoliation, and (3) rapid progression of bacteria toward the lamina propria. In non-CF grafts, these three sets of events were not observed before 6 h. Using a model of naive human airways, we thus demonstrate that before any infection, CF airways are in a proinflammatory state. After infection, the basal inflammatory imbalance contributes to exert severe damage to the mucosa, paving the way for bacterial colonization and subsequent steps of CF airway disease.
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PMID:Inflammation and infection in naive human cystic fibrosis airway grafts. 1091 74

Endothelin (ET)-1 has been suggested to promote neutrophil adhesion to endothelium, migration to inflamed areas, and release of elastase. ET-1 might therefore play a role in the pathogenesis of bronchiectasis, a chronic inflammatory and infective airway disease which is still poorly understood. Thirty five patients with stable bronchiectasis (20 females, mean age+/-SD 49.1+/-15.0 yrs) and 18 control subjects (8 females, 49.4+/-11.3 yrs) were recruited prospectively. The ET-1 levels in serum and sputum were measured by commercially available enzyme linked immunosorbent assay (ELISA) kits. Patients with Pseudomonas aeruginosa in their sputum had a significantly higher serum level of ET-1 (median 25.8, interquartile range 13-43.9 pg x mL(-1)) than patients without P. aeruginosa (0, 0-10.5 pg x mL(-1); p=0.0004) and healthy control subjects (4.6, 0-16.3 pg x mL(-1); p=0.002). However, patients with and without P. aeruginosa infection had no significant difference in sputum ET-1 level (p=0.15). There was no correlation between serum or sputum ET-1 levels with the serum and sputum levels of the interleukin (IL)-1beta, IL-8 and tumour necrosis factor (TNF)-alpha; the number of bronchiectasis lung lobes; and spirometry. Serum ET-1 level correlated with 24 h sputum volume for the bronchiectasis patients (r=0.51, p=0.002). The results, therefore, suggest a significant pathogenic role for endothelin-1 among Pseudomonas aeruginosa-infected patients with bronchiectasis. Further studies should be performed to evaluate the clinico-pathological correlation and expression of endothelin-1 in bronchiectasis.
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PMID:Endothelin-1 in stable bronchiectasis. 1093 1

To determine the effect of Pseudomonas aeruginosa exotoxin A (P-ExA) on cytokine production, we studied cytokine release induced by heat-killed P. aeruginosa (HKPA) in human whole blood in the presence or absence of P-ExA. P-ExA (0.01-1 microgram ml(-1)) caused a dose-dependent decrease in HKPA-induced production of tumor necrosis factor alpha (TNF), interleukin (IL-) 10, IL-6 and IL-8 (all P<0.05). P-ExA-induced inhibition of IL-10, IL-6 and IL-8 release was not dependent on reduced TNF concentrations, since the relative attenuation of the production of these cytokines was similar in the presence or absence of a neutralizing anti-TNF antibody. The effect of P-ExA on cytokine production may offer a disadvantage to the host with respect to clearance of the infection.
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PMID:The effect of pseudomonas exotoxin A on cytokine production in whole blood exposed to Pseudomonas aeruginosa. 1106 70

Pseudomonas aeruginosa infection frequently complicates lung injury and can be fatal in immunocompromised or debilitated individuals. Previous studies from our laboratory indicate that elastase from P. aeruginosa increases epithelial permeability by disrupting tight junctions between epithelial cells. Because the inflammatory reaction of the host is a prominent feature of bacterial infection, we reasoned that additional virulence factors from this organism could extend and augment the initial pulmonary injury by prompting accumulation of neutrophils. To test this hypothesis, we compared responses of guinea pigs to aerosols of elastase (PE) and lipopolysaccharide (LPS) from P. aeruginosa. After each treatment, we measured epithelial permeability and accumulation of neutrophils, interleukin 8 (IL-8), and beta-glucuronidase in epithelial lining fluid (ELF). We found that PE increased epithelial permeability, as measured by both the clearance of aerosolized radiolabeled albumin from the air spaces and the concentration of plasma albumin in epithelial lining fluid, but it was less effective than LPS at recruiting neutrophils into the lungs. In contrast, LPS had no significant effect on epithelium, but it increased the concentration of neutrophils, IL-8, and beta-glucuronidase in ELF. Increased epithelial permeability induced by PE does not cause lung inflammation, but it may facilitate the LPS-induced influx of neutrophils.
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PMID:Virulence factors from Pseudomonas aeruginosa increase lung epithelial permeability. 1114 11

A tendency toward excessive inflammation in cystic fibrosis (CF) patients often accompanies lung infections with Pseudomonas aeruginosa. We tested the cytokine response to P. aeruginosa in two pairs of human airway epithelial cell lines matched except for CF transmembrane conductance regulator activity. The 9/HTEo(-) CF-phenotypic cell line produced significantly more interleukin (IL)-8, IL-6, and granulocyte-macrophage colony-stimulating factor but not regulated on activation normal T cell expressed and secreted (RANTES) in response to Pseudomonas than the 9/HTEo(-) control line, and the differences widened over time. Similarly, a 16HBE cell line lacking transmembrane conductance regulator activity showed enhanced IL-8 and IL-6 responses compared with the control cell line. The pharmacology of the cytokine response also differed because dexamethasone reduced cytokine production to similar levels in the matched cell lines. The protracted proinflammatory cytokine response of the CF-phenotypic cell lines suggests that the limiting mechanisms of normal cells are absent or attenuated. These results are consistent with in vivo observations in patients with CF and suggest that our novel cell lines may be useful for further investigation of the proinflammatory responses in CF airways.
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PMID:Proinflammatory cytokine responses to P. aeruginosa infection in human airway epithelial cell lines. 1115 33

It is unclear whether inflammation in the cystic fibrosis (CF) lung relates predominantly to bacterial infection, or occurs as a direct consequence of mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. Interleukin (IL)-8 secretion from CF and non-CF cell lines, and from CF and non-CF human primary nasal epithelial cells incubated with or without Pseudomonas aeruginosa, was measured. Activation of nuclear factor-kappaB (NF-kappaB) in unstimulated CF and non-CF nasal epithelial cells, cell lines and murine tissues was measured by gel-shift assays. No significant difference in basal IL-8 production or NF-kappaB activation was observed between CF and non-CF primary nasal cells. However, CF cells exhibited a significantly (p<0.01) increased IL-8 secretion following P. aeruginosa stimulation. Equalization of the increased P. aeruginosa adherence observed in CF cells, to non-CF levels, resulted in comparable IL-8 secretion. Further, IL-8 production did not differ with mutations which result in either correctly localized CFTR, or in partial/total mislocalization of this protein. Similar levels of NF-kappaB activation were observed in a number of organs of wildtype and CF mice. Finally, IL-8 secretion and NF-kappaB activity were not consistently increased in CF cell lines. Cos-7 cell transfection with plasmids expressing deltaF508 or G551D mutant CFTR protein resulted in increased activation of a p50-containing NF-kappaB complex, but IL-8 secretion was similar to wild-type cells. The authors conclude that the stimulus produced by Pseudomonas aeruginosa is the predominant inflammatory trigger in their models.
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PMID:Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence. 1130 53

The mechanisms underlying the therapeutic efficacy of erythromycin (EM) in diffuse panbronchiolitis (DPB) was investigated. For this purpose, an experimental rabbit model of DPB induced by Pseudomonas aeruginosa inoculation was employed. Daily administration of EM (3 mg x kg x day(-1)) led to an increase in the number of macrophages in bronchoalveolar lavage fluid (BALF) at an early phase, while reducing the size of granulomatous lesions at the late phase without affecting the number of viable bacteria recovered from the infected lung. Reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemical studies showed that monocyte chemoattractant protein (MCP)-1 was produced in both BALF and infected lung. EM treatment resulted in a significant increase in the level of MCP-1 in BALF, while reducing that of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8. EM also increased MCP-1 messenger ribonucleic acid (mRNA) and protein expression in the infected lung. MCP-1 blockade abolished the protective effect of EM, as neutralization of MCP-1 with anti-MCP-1 antibodies reduced the EM-induced increase in the number of macrophages in BALF, and augmented size of the granulomatous lesions, as compared to control. The results of the present study suggest that erythromycin attenuates the pulmonary granuloma formation, at least in part, by increasing the production of monocyte chemoattractant protein-1.
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PMID:Erythromycin attenuates an experimental model of chronic bronchiolitis via augmenting monocyte chemoattractant protein-1. 1140 12

The destructive pulmonary inflammation associated with Pseudomonas aeruginosa colonization is caused, in part, by the production of the chemokine IL-8, which recruits neutrophils into the lung. The Pseudomonas autoinducer, N-3-oxododecanoyl homoserine lactone (3-O-C12-HSL), is a small lipid-soluble molecule that is essential in the regulation of many P. aeruginosa virulence factors, but little is known about how it affects eukaryotic cells. In this report we demonstrate that 3-O-C12-HSL is a potent stimulator of both IL-8 mRNA and protein from human fibroblasts and epithelial cells in vitro. The IL-8 produced from these 3-O-C12-HSL-stimulated cells was found to be functionally active by inducing the chemotaxis of neutrophils. To determine a mechanism for this IL-8 induction, deletion constructs of the IL-8 promoter were examined. It was found that the DNA region between nucleotides -1481 and -546 and the transcription factor NF-kappaB were essential for the maximal induction of IL-8 by 3-O-C12-HSL. This was confirmed by EMSAs, where 3-O-C12-HSL induced a shift with both AP-2 and NF-kappaB consensus DNA. The activation of NF-kappaB and subsequent production of IL-8 were found to be regulated by a mitogen-activated protein kinase pathway. These findings support the concept that the severe lung damage that accompanies P. aeruginosa infections is caused by an exuberant neutrophil response stimulated by 3-O-C12-HSL-induced IL-8. Understanding the mechanisms of 3-O-C12-HSL activation of lung structural cells may provide a means to help control lung damage during infections with P. aeruginosa.
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PMID:IL-8 production in human lung fibroblasts and epithelial cells activated by the Pseudomonas autoinducer N-3-oxododecanoyl homoserine lactone is transcriptionally regulated by NF-kappa B and activator protein-2. 1141 72


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