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

Epithelial cells represent the initial site of bacterial colonization in the respiratory tract. TLR9 has been identified in B cells and CD 123(+) dendritic cells and found to be involved in the recognition of microbial DNA. It was the aim of the study to investigate the role of TLR9 in the host defense reactions of the respiratory epithelium. Respiratory epithelial cell lines (IHAEo(-), Calu-3) or fully differentiated primary human cells as air-liquid interface cultures were stimulated with bacterial DNA or synthetic oligonucleotides containing CpG motifs (CpG oligodeoxynucleotides). Expression of TLR9, cytokines, and human beta-defensin 2 was determined by quantitative RT-PCR or by ELISA. We found that TLR9 is expressed by respiratory epithelial cell lines and fully differentiated primary epithelial cells at low levels. Stimulation of the above-mentioned cells with bacterial DNA or CpG oligodeoxynucleotide resulted in an inflammatory reaction characterized by a dose-dependent up-regulation of cytokines (IL-6, IL-8) and human beta-defensin 2. Up-regulation of NF-kappaB in epithelial cells in response to the CpG motif containing DNA was inhibited by overexpression of a dominant negative form of MyD88. These results provide clear evidence that the human respiratory epithelium is capable of detecting microbial DNA by TLR9. The respiratory epithelium has an important function in triggering innate immune responses and therefore represents an interesting target for anti-inflammatory therapy.
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PMID:Microbial DNA induces a host defense reaction of human respiratory epithelial cells. 1524 Jul 13

Intracellular oxidation and reduction (redox state) correspond closely to the surrounding environment. Most environmental factors affecting this balances such as oxidants, ultraviolet light, radioactive emissions, infections, and allergic reactions represent oxidative stress upon cells. We examined intracellular redox state after oxidative stress upon cultured human airway epithelial cells (Calu-3) by measuring reduced (GSH) or oxidized (GSSG) glutathione. We studied cytokine production, which is related to glutathione redox regulation, in response to ozone and also evaluated the effect of pretreatment with an ethyl ester of reduced glutathione (GSH-OEt) on cytokines. Ozone exposure (3.0 ppm, 3 min) time-dependently changed the redox state, while increasing production of interleukin(IL)-8 and IL-6, mRNA and protein. Treatment with GSH-OEt before ozone suppressed IL-8, but stimulated IL-6 production. Thus, oxidative stress affects intracellular glutathione redox state, in airway epithelial cells, activating signals to increase production of cytokine, modulation that may exacerbate respiratory symptoms.
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PMID:Effect of ozone exposure on intracellular glutathione redox state in cultured human airway epithelial cells. 1537 16

Neither Pseudomonas aeruginosa nor flagellin affected cytosolic Ca(2+) concentration ([Ca](i)) in airway epithelial cell lines JME and Calu-3, but bacteria or flagellin activated NF-kappaB, IL-8 promoter, and IL-8 secretion. ATP (purinergic agonist) and thapsigargin (blocks Ca(2+) pump, releases endoplasmic reticulum Ca(2+), and triggers Ca(2+) entry through plasma membrane channels) both increased [Ca](i) but hardly stimulated NF-kappaB and IL-8. ATP and thapsigargin elicited larger, synergistic activations of NF-kappaB and IL-8 secretion when combined with flagellin. BAPTA-AM (to buffer [Ca](i)) or Ca(2+)-free solution reduced increases in [Ca](i) due to ATP or thapsigargin and also reduced NF-kappaB activation and IL-8 secretion triggered by flagellin, ATP, thapsigargin, ATP + flagellin, and thapsigargin + flagellin. IL-8 promoter analysis showed that AP-1 and CCAAT/enhancer-binding protein (C/EBP)beta/nuclear factor for IL-6 (NF-IL6) sites were important for IL-8 expression, and the NF-kappaB-binding site was critical for activation by all agonists and for activation by [Ca](i). Thus increased [Ca](i) was not required for P. aeruginosa- or flagellin-activated NF-kappaB and IL-8 expression and secretion, and increased [Ca](i) was only weakly stimulatory during activation by ATP or thapsigargin. However, ATP- or thapsigargin-induced increases in [Ca](i) synergized with flagellin or P. aeruginosa, and buffering or reducing [Ca](i) reduced these responses. Thus [Ca](i) plays an important regulatory role in P. aeruginosa- or flagellin-activated innate immune responses in airway epithelia. Dose-dependent responses indicated that flagellin-ATP synergism occurred most prominently at ATP concentrations ([ATP]) > 10 microM and [flagellin] >10(-8) g/ml and during steady increases rather than oscillations in [Ca](i).
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PMID:Role of Ca2+ in responses of airway epithelia to Pseudomonas aeruginosa, flagellin, ATP, and thapsigargin. 1696 31

In the airway epithelia, extracellular adenosine modulates a number of biological processes. However, little is known about adenosine's role in the inflammatory responses of airway epithelial cells. Recent studies suggest that the chronic elevation of extracellular adenosine in mice leads to pulmonary inflammation and fibrosis. Yet, the underlying molecular mechanism has not been well understood and little attention has been paid to the role of airway epithelia in adenosine-triggered inflammation. In the present work, we examined the role of adenosine in releasing IL-6 from airway epithelia. In Calu-3 human airway epithelial cells, apical but not basolateral adenosine elicited robust, apically polarized release of IL-6, along with proinflammatory IL-8. Both protein kinase A and protein kinase C mediated the adenosine-induced IL-6 release, at least partly via phosphorylation of CREB. Protein kinase C appeared to phosphorylate CREB through activating ERK. In addition, A2A but not A2B adenosine receptors were specifically required for the adenosine-induced IL-6 release. Furthermore, in rat bronchoalveolar lavage fluid, adenosine triggered the release of IL-6 as well as proinflammatory IL-1beta. Adenosine also mediated the release of a considerable portion of the LPS-induced IL-6 in rat bronchoalveolar lavage fluid. Our findings provide a possible molecular link between extracellular adenosine elevation and lung inflammation and fibrosis.
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PMID:Adenosine promotes IL-6 release in airway epithelia. 1832 29

Exogenous surfactant is critical in the treatment of neonates with respiratory distress syndrome. Lucinactant (Surfaxin; Discovery Laboratories, Inc.) is a surfactant replacement therapy containing sinulpeptide, which may reduce lung inflammation. This study tested whether Lucinactant reduces markers of inflammation, damage and remodeling in human airway epithelial cells exposed to hyperoxia. Calu-3 monolayers cultured at an air-liquid interface were treated apically with 140 microL of normal saline, Lucinactant or Beractant (Survanta; Abbott Laboratories, Inc.). Treated monolayers were exposed to 60% O(2)/5% CO(2) for 24 or 72 h. Transepithelial resistance (TER; p < 0.001) and cell viability (p < 0.05) were greater in both surfactant groups compared with saline; by 72 h Lucinactant cells had greater TER than Beractant (p < 0.001). Surfactant treated groups secreted less IL-8 than saline (p < 0.001), whereas Lucinactant cells secreted less IL-6 than saline and Beractant (p < 0.001). Matrix metalloproteinase 7, expressed by saline and Beractant treated cells at 24 h, was attenuated by 72 h by Beractant (p < 0.001), but was never detected in Lucinactant cells. Histology indicated less injury with Lucinactant relative to Beractant and saline. These data suggest that Lucinactant was protective compared with Beractant and control.
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PMID:KL4-surfactant (Lucinactant) protects human airway epithelium from hyperoxia. 1839 44

The aim of this study was to compare protein-loaded inhalable microparticles manufactured using a range of biocompatible polymers including hydroxypropyl cellulose (HPC), chitosan, hyaluronic acid, alginate, gelatin, ovalbumin and poly(lactide-co-glycolide) (PLGA). Spray-drying was used to prepare microparticles containing bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC). Particles of respirable size and high protein loading were obtained. No evidence of BSA degradation was seen from PAGE analysis. The microparticles were mixed with mannitol as a carrier and powder aerosolization was assessed with a multi-dose dry powder inhaler (DPI) using a multi-stage cascade impactor. The mass median aerodynamic diameter (MMAD) ranged between 2.9 and 4.7 microm. Potential polymer toxicity in the lungs was compared by impinging the particles on Calu-3 monolayers and assessing the cytotoxicity, induction of cytokine release, changes in transepithelial permeability and electrical resistance. No toxic effects were observed with most of the polymers though some evidence of compromised cell monolayer integrity was seen for PLGA and ovalbumin. PLGA and gelatin microparticles caused a significant increase in IL-8 release. Of the polymers studied, PLGA showed the greatest toxicity. Certain polymers showed particular promise for specific protein delivery needs in the lungs, such as HPC to improve flow properties, sodium hyaluronate for controlled release, and chitosan and ovalbumin for systemic delivery.
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PMID:A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins. 1844 88

Rosette nanotubes (RNT) are a new class of metal-free organic nanotubes synthesized through self-assembly. Because of the wide range of potential biomedical applications associated with these materials, it is necessary to evaluate their potential in vitro toxicity. Here the cytotoxicity of a lysine-functionalized nanotube (RNT-K) in a human Calu-3 pulmonary epithelial cell line is investigated. The cells were treated with media only (control), lysine (50 mg mL(-1)), RNT-K (1, 5, and 50 microg mL(-1)), Min-U-Sil quartz microparticles (QM; 80 microg mL(-1)), and lipopolysaccharide (LPS; 1 microg mL(-1)). The supernatants were analyzed at 1, 6, and 24 h after treatment for the expression of three proinflammatory mediators: IL-8, TNF-alpha and EMAP-II. Cellular viability determined with the Trypan blue assay is significantly reduced in the QM and high-dose RNT-treated groups. TNF-alpha and EMAP-II are undetectable by enzyme-linked-immunosorbent assay (ELISA) in the supernatant of all groups. Although IL-8 concentrations do not differ between treatments, its concentrations increase with time within each of the groups. Quantitative reverse-transcriptase polymerase chain reaction (qRTPCR) of IL-8 mRNA shows increased expression in the high-dose RNT-treated groups at both 1 and 6 h, while an adhesion molecule, ICAM-1 mRNA, shows the greatest increase at 6 h in the QM-treated group. In summary, RNT-K neither reduces cell viability at moderate doses nor does it induce a time-dependent inflammatory response in pulmonary epithelial cells in vitro.
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PMID:Low inflammatory activation by self-assembling Rosette nanotubes in human Calu-3 pulmonary epithelial cells. 1853 89

Long-chain n-3 PUFA (LCn-3PUFA) including DHA and EPA, are known to decrease inflammation by inhibiting arachidonic acid (AA) metabolism to eicosanoids, decreasing the production of pro-inflammatory cytokines and reducing immune cell function. The aim of this study was to determine if EPA and DHA reduced the release of inflammatory mediators from airway epithelial cells infected with rhinovirus (RV). Airway epithelial cells (Calu-3) were incubated with EPA, DHA and AA for 24 h, followed by rhinovirus infection for 48 h. IL-6, IL-8 and interferon-gamma-induced protein-10 (IP-10) released by cells were measured using ELISA. Viral replication was measured by serial titration assays. The fatty acid content of cells was analysed using GC. Cellular viability was determined by visual inspection of cells and lactate dehydrogenase release. DHA (400 microm) resulted in a significant 16% reduction in IL-6 release after RV-43 infection, 29% reduction in IL-6 release after RV-1B infection, 28% reduction in IP-10 release after RV-43 infection and 23 % reduction in IP-10 release after RV-1B infection. Cellular DHA content negatively correlated with IL-6 and IP-10 release. None of the fatty acids significantly modified rhinovirus replication. DHA supplementation resulted in increased cellular content of DHA at the cost of AA, which may explain the decreased inflammatory response of cells. EPA and AA did not change the release of inflammatory biomarkers significantly. It is concluded that DHA has a potential role in suppressing RV-induced airway inflammation.
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PMID:Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured airway epithelial cells. 1863 17

Activation of an innate immune response in airway epithelia by the human pathogen Pseudomonas aeruginosa requires bacterial expression of flagellin. Addition of flagellin (10(-7) M) to airway epithelial cell monolayers (Calu-3, airway serous cell-like) increased Cl(-) secretion (I(Cl)) beginning after 3-10 min, reaching a plateau after 20-45 min at DeltaI(Cl) = 15-50 microA/cm(2). Similar, although 10-fold smaller, responses were observed in well-differentiated bronchial epithelial cultures. Flagellin stimulated I(Cl) in the presence of maximally stimulating doses of the purinergic agonist ATP, but had no effects following forskolin. IL-1beta (produced by both epithelia and neutrophils during infections) stimulated I(Cl) similar to flagellin. Flagellin-, IL-1beta-, ATP-, and forskolin-stimulated I(Cl) were inhibited by cystic fibrosis transmembrane conductance regulator (CFTR) blockers GlyH101, CFTRinh172, and glibenclamide. Neither flagellin nor IL-1beta altered transepithelial fluxes of membrane-impermeant dextran (10 kDa) or lucifer yellow (mol wt = 457), but both activated p38, NF-kappaB, and IL-8 secretion. Blockers of p38 (SB-202190 and SB-203580) reduced flagellin- and IL-1beta-stimulated I(Cl) by 33-50% but had smaller effects on IL-8 and NF-kappaB. It is concluded that: 1) flagellin and IL-1beta activated p38, NF-kappaB, IL-8, and CFTR-dependent anion secretion without altering tight junction permeability; 2) p38 played a role in regulating I(Cl) and IL-8 but not NF-kappaB; and 3) p38 was more important in flagellin- than IL-1beta-stimulated responses. During P. aeruginosa infections, flagellin and IL-1beta are expected to increase CFTR-dependent ion and fluid flow into and bacterial clearance from the airways. In cystic fibrosis, the secretory response would be absent, but activation of p38, NF-kappaB, and IL-8 would persist.
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PMID:Flagellin-stimulated Cl- secretion and innate immune responses in airway epithelia: role for p38. 1865 72

We tested the hypothesis that hyperoxia or pressure exposure differentially activates expression of cytokines and/or matrix modeling proteins in human airway epithelial cells. Calu-3 epithelial cell monolayers were cultured on transwell plates with the apical surface exposed to gas. Following establishment of baseline, plates were placed in a chamber and exposed to: control (21% O (2); atm), hyperoxia (60% O (2); atm), pressure (21% O (2); 40 cm H (2)O), and combination (60% O (2); 40 cm H (2)O). At 72 hour of exposure, monolayers were assessed for integrity, viability, and expression of interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMPs) -2, -7, and -9. Compared with controls, hyperoxia had lower transepithelial resistance ( P < 0.001) and greater IL-6 secretion ( P < 0.01), and pressure had lower cell viability ( P < 0.001) and greater IL-8 secretion ( P < 0.001). Hyperoxia resulted in more latent MMP-2 ( P < 0.05) and MMP-7 ( P < 0.001). Pressure was associated with a rise in MMPs independent of oxygen exposure ( P < 0.05). Hyperoxia and pressure differentially affected MMP activities in Calu-3 cells and may lead to the different functional and structural abnormalities observed in these in vitro studies.
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PMID:Dissociation between the effects of oxygen and pressure on matrix metalloproteinase-2, -7, and -9 expression in human airway epithelial cells. 1872 Mar 22


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