scholarly journals 2301 Mucoidal pseudomonas aeruginosa infection is associated with regional inflammation in the cystic fibrosis lung

2018 ◽  
Vol 2 (S1) ◽  
pp. 20-21
Author(s):  
Sankalp Malhotra ◽  
Daniel J. Wozniak ◽  
Don Hayes
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Lower Lobe ◽  
Left Lower Lobe ◽  
Microbiological Analysis ◽  
Tnf Α ◽  
Mixed Populations ◽  
Lung Lobes

OBJECTIVES/SPECIFIC AIMS: Cystic fibrosis (CF) is a life-shortening genetic disease that affects approximately 30,000 patients in the United States. CF patients suffer from chronic pulmonary infections that are associated with hyperinflammation and irreversible damage to the lower airways. As CF patients age, Pseudomonas aeruginosa (P.a.) is the predominant pathogen that infects the respiratory tract. The P.a. strains initially infecting the CF lung have a nonmucoid colony morphology, whereas, once chronic infection is established, these bacteria mutate leading to the emergence of mucoid P.a. variants with heightened resistance to both antibiotics and host immunity. Both nonmucoid and mucoid P.a. variants are often co-isolated on microbiological cultures of sputum collected from CF patients. However, the CF lung is known to exhibit heterogeneity in inflammation and infecting microbes across different lung regions that cannot be studied using routine sputum collection alone. Here, using a standardized bronchoscopic protocol, bronchoalveolar lavage (BAL) fluid was prospectively collected from each lobe of a CF cohort undergoing clinically indicated surgical procedures. We sought to investigate if there is an association between infecting P.a. variants (nonmucoid, mucoid, or mixed populations), the lung lobes in which these variants are found, and regional proinflammatory cytokine production. METHODS/STUDY POPULATION: We performed BAL on 16 CF patients with clinically stable disease. For each patient, we obtained BAL fluid from the right upper lobe, right middle lobe, right lower lobe, left upper lobe, lingula, and left lower lobe. We plated BAL fluid on nonselective and P.a.-selective medium to quantitate bacteria and to identify P.a. colony subtypes (nonmucoid, mucoid, or mixed). We further used a V-PLEX human cytokine array to quantitate inflammatory cytokine concentrations (IL-1β, TNF-α, IL-6, IL-8, and IL-10) within BAL fluid specimens. Our specimen collection was approved by the local IRB with informed consent and assent obtained from patient volunteers. RESULTS/ANTICIPATED RESULTS: Based on microbiological analysis, each lobar BAL specimen was classified as uninfected with P. a. or infected with nonmucoid, mucoid, or mixed (both nonmucoid and mucoid) P.a. variants. There was no observed propensity of mucoid or nonmucoid variants to be confined to certain lung lobes in our cohort. However, infection with mucoid P.a. variants was associated with higher concentrations of IL-1β (p<0.001), TNF-α (p<0.001), IL-8 (p<0.001), and IL-10 (p<0.001) within lobar BAL fluid compared with P.a.-free specimens. Specimens with mucoid variants also had greater concentrations of TNF-α (p<0.01), IL-8 (p<0.001), and IL-10 (p<0.05) compared with specimens with only nonmucoid P.a. variants. Patients infected with mixed mucoid and nonmucoid variants showed higher concentrations of TNF-α and IL-10 (p<0.05) as well as nonsignificant trends for higher concentrations of IL-1β and IL-6 compared to P.a.-free samples. Interestingly, the presence of nonmucoid P.a. variants was inversely correlated with IL-6 (p<0.05). Total bacterial burden (both P.a. and non-P.a. species) within BAL fluids was positively correlated with higher proinflammatory cytokine concentrations. Additionally, independent of bacterial colonization, the upper lobes (right upper lobe and left upper lobe) of the lungs showed trends towards higher proinflammatory cytokine concentrations compared with the lower lobes (right lower lobe and left lower lobe). DISCUSSION/SIGNIFICANCE OF IMPACT: Our results demonstrate that P.a. variants (mucoid or nonmucoid) appear not to be geographically restricted in ability to colonize any lobe of the CF lung. Moreover, infection with mucoid P.a. (either alone or in mixed populations with nonmucoid variants) is associated with higher inflammatory cytokine concentrations in the CF lung. Given that infection with mucoid P.a. predicts deterioration in pulmonary function, this study provides a rationale for further investigation of cytokines as diagnostic/prognostic correlates of infection and lung disease in CF.

Ivacaftor partially corrects airway inflammation in a humanized G551D rat

2021 ◽  
Author(s):  
Morgan Green ◽  
Natalie R Lindgren ◽  
Alexander G Henderson ◽  
Johnathan D Keith ◽  
Ashley M Oden ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Animal Models ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Inflammatory Stimulus ◽  
Cytokine Concentration ◽  
Rat Models ◽  
Neutrophil Influx ◽  
Tnf Α ◽  
Inflammatory Changes

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when CFTR activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.

scholarly journals The Anti-Pseudomonal Peptide D-BMAP18 Is Active in Cystic Fibrosis Sputum and Displays Anti-Inflammatory In Vitro Activity

2020 ◽  
Vol 8 (9) ◽  
pp. 1407
Author(s):  
Margherita Degasperi ◽  
Chiara Agostinis ◽  
Mario Mardirossian ◽  
Massimo Maschio ◽  
Andrea Taddio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Dnase I ◽  
Starting Point ◽  
Tnf Α ◽  
Specific Cytotoxicity ◽  
Ifn Γ ◽  
Lung Infections ◽  
Anti Inflammatory

Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to Pseudomonas aeruginosa. D-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of D-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of Pseudomonas aeruginosa in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, D-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some P. aeruginosa strains. In addition, D-BMAP18 down regulated the production of TNF-α, IL1-β, and TGF-β in LPS-stimulated or IFN-γ macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of D-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that D-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients.

scholarly journals Innate Lung Defenses and Compromised Pseudomonas aeruginosa Clearance in the Malnourished Mouse Model of Respiratory Infections in Cystic Fibrosis

2000 ◽  
Vol 68 (4) ◽  
pp. 2142-2147 ◽  
Author(s):  
H. Yu ◽  
S. Z. Nasr ◽  
V. Deretic
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Knockout Mice ◽  
Respiratory Infections ◽  
Bacterial Colonization ◽  
Interleukin 10 ◽  
High Morbidity ◽  
Necrosis Factor Alpha ◽  
Pulmonary Clearance ◽  
Tnf Α

ABSTRACT Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections. Chronic lung infections withPseudomonas aeruginosa, intense neutrophil-dominated airway inflammation, and progressive lung disease are the major cause of high morbidity and mortality in CF. Here we investigated the effects of malnutrition in CF on innate lung defenses, susceptibility to P. aeruginosa colonization, and associated inflammation, using aerosol models of acute and chronic infections in normal, malnourished, and transgenic mice. CFTRm1Unc−/− knockout mice displayed body weight variations and showed variable pulmonary clearance of P. aeruginosa. This variability was not detected in bitransgenicCFTRm1Unc−/− (FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutrition in C57BL/6J mice resulted in impaired pulmonary clearance of P. aeruginosa. Tumor necrosis factor alpha (TNF-α) and nitrite levels detected upon exposure to P. aeruginosaaerosols were lower in the lungs of the malnourished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role of TNF-α and reactive nitrogen intermediates in P. aeruginosaclearance was tested in TNF-α and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was diminished in transgenic TNF-α- and iNOS-deficient mice. In contrast to the effects of TNF-α and iNOS, gamma interferon knockout mice retained a full capacity to eliminate P. aeruginosafrom the lung. Malnutrition also contributed to excessive inflammation in C57BL/6J mice upon chronic challenge with P. aeruginosa. The repeatedly infected malnourished host did not produce interleukin-10, a major anti-inflammatory cytokine absent or diminished in the bronchoalveolar fluids of CF patients. These results are consistent with a model in which defective CFTR in the intestinal tract leads to nutritional deficiency which in turn contributes to compromised innate lung defenses, bacterial colonization, and excessive inflammation in the CF respiratory tract.

scholarly journals Supplementation of xanthophylls decreased proinflammatory and increased anti-inflammatory cytokines in hens and chicks

2012 ◽  
Vol 108 (10) ◽  
pp. 1746-1755 ◽  
Author(s):  
Yu-Yun Gao ◽  
Qing-Mei Xie ◽  
Ling Jin ◽  
Bao-Li Sun ◽  
Jun Ji ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Control Group ◽  
In Ovo ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Different Tissues

The present study investigated the effects of xanthophylls (containing 40 % of lutein and 60 % of zeaxanthin) on proinflammatory cytokine (IL-1β, IL-6, interferon (IFN)-γ and lipopolysaccharide-induced TNF-α factor (LITAF)) and anti-inflammatory cytokine (IL-4 and IL-10) expression of breeding hens and chicks. In Expt 1, a total of 432 hens were fed diets supplemented with 0 (as the control group), 20 or 40 mg/kg xanthophylls (six replicates per treatment). The liver, duodenum, jejunum and ileum were sampled at 35 d of the trial. The results showed that both levels of xanthophyll addition decreased IL-1β mRNA in the liver and jejunum, IL-6 mRNA in the liver, IFN-γ mRNA in the jejunum and LITAF mRNA in the liver compared to the control group. Expt 2 was a 2 × 2 factorial design. Male chicks hatched from 0 or 40 mg/kg xanthophyll diet of hens were fed a diet containing either 0 or 40 mg/kg xanthophylls. The liver, duodenum, jejunum and ileum were collected at 0, 7, 14 and 21 d after hatching. The results showed thatin ovoxanthophylls decreased proinflammatory cytokine expression (IL-1β, IL-6, IFN-γ and LITAF) in the liver, duodenum, jejunum and ileum and increased anti-inflammatory cytokine expression (IL-4 and IL-10) in the liver, jejunum and ileum mainly at 0–7 d after hatching.In ovoeffects gradually vanished and dietary effects began to work during 1–2 weeks after hatching. Dietary xanthophylls modulated proinflammatory cytokines (IL-1β, IL-6 and IFN-γ) in the liver, duodenum, jejunum and ileum and anti-inflammatory cytokine (IL-10) in the liver and jejunum mainly from 2 weeks onwards. In conclusion, xanthophylls could regulate proinflammatory and anti-inflammatory cytokine expression in different tissues of hens and chicks.

The Expression of Inflammatory Cytokine and Heme Oxygenase-1 Genes in THP-1 Cells Exposed to Metal Oxide Nanoparticles

2015 ◽  
Vol 30 ◽  
pp. 116-127 ◽  
Author(s):  
Masanori Horie ◽  
Keiko Nishio ◽  
Haruhisa Kato ◽  
Shigehisa Endoh ◽  
Katsuhide Fujita ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Metal Oxide Nanoparticles ◽  
The Other ◽  
Heme Oxygenase 1 ◽  
Nio Nanoparticles ◽  
Cytokine Genes ◽  
Tnf Α ◽  
Nanoparticle Solubility

The effect of manufactured nanoparticles on the expression of proinflammatory cytokine genes was examined. THP-1 cells differentiated into macrophage cells were exposed to TiO2 and NiO medium dispersions. After 2, 6, 12, or 24 hours exposure, the expression of IL-1β, IL-6, IL-8, TNF-α and HO-1 genes was determined by real-time PCR. TiO2 nanoparticles did not affect cytokine production. In addition, TiO2 nanoparticles did not dissolve in the dispersion. On the other hand, NiO nanoparticles enhanced the expression of all the genes tested. NiO dispersions were composed of 58.3 μg/mL of NiO nanoparticles and 45.8 μg/mL of Ni2+. The release of metal ions from the nanoparticles is associated with their cytotoxicity. Therefore, the effect of an NiCl2 solution containing 45.8 μg/mL of Ni2+ on the expression of cytokine genes was also examined. The effects of NiCl2 were similar to those of the NiO nanoparticles. Furthermore, the effect of ZnO, SiO2-coated ZnO, Sb2O3, and Cr2O3 nanoparticles on the expression of IL-1β, IL-8 and TNF-α genes was examined. Soluble nanoparticles, such as ZnO, SiO2-coated ZnO, and Cr2O3 enhanced the gene expression of cytokines. Sb2O3 nanoparticles showed poor solubility and did not affect the expression of cytokine genes. In conclusion, these results suggest that nanoparticle solubility plays an important role in regulating the expression of proinflammatory cytokines.

scholarly journals γδ T lymphocytes from cystic fibrosis patients and healthy donors are high TNF-α and IFN-γ-producers in response to Pseudomonas aeruginosa

2003 ◽  
Vol 4 (1) ◽  
Author(s):  
Salvador Raga ◽  
M Rosa Julià ◽  
Catalina Crespí ◽  
Joan Figuerola ◽  
Natalia Martínez ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
T Lymphocytes ◽  
Healthy Donors ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Gene silencing of the pro-inflammatory cytokine TNF-α with siRNA delivered by calcium phosphate nanoparticles, quantified by different methods

2015 ◽  
Vol 3 (36) ◽  
pp. 7186-7193 ◽  
Author(s):  
Bernhard Neuhaus ◽  
Annika Frede ◽  
Astrid Maria Westendorf ◽  
Matthias Epple
Keyword(s):  
Calcium Phosphate ◽  
Gene Silencing ◽  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Inflammatory Reactions ◽  
Tnf Α ◽  
Calcium Phosphate Nanoparticles

The expression of the proinflammatory cytokine TNF-α was efficiently downregulated with nanoparticles, opening a way to combat inflammatory reactions.

Inhibition of Pro-Inflammatory Cytokine Secretion by Select Antioxidants in Human Coronary Artery Endothelial Cells

2020 ◽  
Vol 90 (1-2) ◽  
pp. 103-112 ◽  
Author(s):  
Michael J. Haas ◽  
Marilu Jurado-Flores ◽  
Ramadan Hammoud ◽  
Victoria Feng ◽  
Krista Gonzales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ascorbic Acid ◽  
Coronary Artery ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Culture Media ◽  
Cytokine Secretion ◽  
Human Coronary Artery ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract. Inflammatory and oxidative stress in endothelial cells are implicated in the pathogenesis of premature atherosclerosis in diabetes. To determine whether high-dextrose concentrations induce the expression of pro-inflammatory cytokines, human coronary artery endothelial cells (HCAEC) were exposed to either 5.5 or 27.5 mM dextrose for 24-hours and interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF α) levels were measured by enzyme immunoassays. To determine the effect of antioxidants on inflammatory cytokine secretion, cells were also treated with α-tocopherol, ascorbic acid, and the glutathione peroxidase mimetic ebselen. Only the concentration of IL-1β in culture media from cells exposed to 27.5 mM dextrose increased relative to cells maintained in 5.5 mM dextrose. Treatment with α-tocopherol (10, 100, and 1,000 μM) and ascorbic acid (15, 150, and 1,500 μM) at the same time that the dextrose was added reduced IL-1β, IL-6, and IL-8 levels in culture media from cells maintained at 5.5 mM dextrose but had no effect on IL-1β, IL-6, and IL-8 levels in cells exposed to 27.5 mM dextrose. However, ebselen treatment reduced IL-1β, IL-6, and IL-8 levels in cells maintained in either 5.5 or 27.5 mM dextrose. IL-2 and TNF α concentrations in culture media were below the limit of detection under all experimental conditions studied suggesting that these cells may not synthesize detectable quantities of these cytokines. These results suggest that dextrose at certain concentrations may increase IL-1β levels and that antioxidants have differential effects on suppressing the secretion of pro-inflammatory cytokines in HCAEC.

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