scholarly journals Enhanced Expression of Human Epididymis Protein 4 (HE4) Reflecting Pro-Inflammatory Status Is Regulated by CFTR in Cystic Fibrosis Bronchial Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Zsolt Bene ◽  
Zsolt Fejes ◽  
Tibor Gabor Szanto ◽  
Ferenc Fenyvesi ◽  
Judit Váradi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Nuclear Translocation ◽  
Patch Clamp Technique ◽  
Bronchial Epithelial ◽  
Human Epididymis Protein 4 ◽  
Protein Levels ◽  
Human Epididymis ◽  
Inflammatory Status ◽  
Tnf Α ◽  
Cftr Modulators

Decreased human epididymis protein 4 (HE4) plasma levels were reported in cystic fibrosis (CF) patients under CFTR potentiator ivacaftor therapy, which inversely correlated with lung function improvement. In this study, we investigated whether HE4 expression was affected via modulation of CFTR function in CF bronchial epithelial (CFBE) cells in vitro. HE4 protein levels were measured in the supernatants of CFBE 41o− cells expressing F508del-CFTR or wild-type CFTR (wt-CFTR) after administration of lumacaftor/ivacaftor or tezacaftor/ivacaftor, while HE4 expression in CFBE 41o− cells were also analyzed following application of adenylate cyclase activators Forskolin/IBMX or CFTRinh172. The effect of all of these compounds on CFTR function was monitored by the whole-cell patch-clamp technique. Induced HE4 expression was studied with interleukin-6 (IL-6) in F508del-CFTR CFBE 41o− cells under TNF-α stimulation for 1 h up to 1 week in duration. In parallel, plasma HE4 was determined in CF subjects homozygous for p.Phe508del-CFTR mutation receiving lumacaftor/ivacaftor (Orkambi®) therapy. NF-κB-mediated signaling was observed via the nuclear translocation of p65 subunit by fluorescence microscopy together with the analysis of IL-6 expression by an immunoassay. In addition, HE4 expression was examined after NF-κB pathway inhibitor BAY 11-7082 treatment with or without CFTR modulators. CFTR modulators partially restored the activity of F508del-CFTR and reduced HE4 concentration was found in F508del-CFTR CFBE 41o− cells that was close to what we observed in CFBE 41o− cells with wt-CFTR. These data were in agreement with decreased plasma HE4 concentrations in CF patients treated with Orkambi®. Furthermore, CFTR inhibitor induced elevated HE4 levels, while CFTR activator Forskolin/IBMX downregulated HE4 in the cell cultures and these effects were more pronounced in the presence of CFTR modulators. Higher activation level of baseline and TNF-α stimulated NF-κB pathway was detected in F508del-CFTR vs. wt-CFTR CFBE 41o− cells that was substantially reduced by CFTR modulators based on lower p65 nuclear positivity and IL-6 levels. Finally, HE4 expression was upregulated by TNF-α with elevated IL-6, and both protein levels were suppressed by combined administration of NF-κB pathway inhibitor and CFTR modulators in CFBE 41o− cells. In conclusion, CFTR dysfunction contributes to abnormal HE4 expression via NF-κB in CF.

Brief murine myocardial I/R induces chemokines in a TNF-α-independent manner: role of oxygen radicals

2001 ◽  
Vol 281 (6) ◽  
pp. H2549-H2558 ◽  
Author(s):  
Tareck O. Nossuli ◽  
Nikolaos G. Frangogiannis ◽  
Pascal Knuefermann ◽  
Venkatesh Lakshminarayanan ◽  
Oliver Dewald ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Radical Scavenger ◽  
Reactive Oxygen Intermediate ◽  
Area At Risk ◽  
Independent Manner ◽  
Protein Levels ◽  
Inflammatory Protein ◽  
Tnf Α ◽  
Venular Endothelium

Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-α, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-α-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-α double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1α, -1β, and -2 at both the mRNA and protein levels. This induction was independent of TNF-α, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-κB and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.

scholarly journals Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis

CHEST Journal ◽  
2016 ◽  
Vol 150 (3) ◽  
pp. 661-672 ◽  
Author(s):  
Béla Nagy ◽  
Béla Nagy ◽  
Libor Fila ◽  
Luka A. Clarke ◽  
Ferenc Gönczy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Human Epididymis Protein 4 ◽  
Inflammatory Biomarker ◽  
Human Epididymis

scholarly journals Anti-Inflammatory and Anti-Oxidant Effect of Dimethyl Fumarate in Cystic Fibrosis Bronchial Epithelial Cells

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2132
Author(s):  
Onofrio Laselva ◽  
Caterina Allegretta ◽  
Sante Di Gioia ◽  
Carlo Avolio ◽  
Massimo Conese
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Dimethyl Fumarate ◽  
Bronchial Epithelial Cells ◽  
Bronchial Epithelial ◽  
Inflammatory Status ◽  
Anti Oxidant ◽  
Anti Inflammatory ◽  
Oxidant Effect

Cystic Fibrosis (CF) is caused by mutations on the CF transmembrane conductance regulator (CFTR) gene and is associated with chronic infection and inflammation. Recently, it has been demonstrated that LPS-induced CFTR dysfunction in airway epithelial cells is due to an early oxidative stress. Dimethyl fumarate (DMF) is an approved anti-inflammatory and anti-oxidant drug for auto-immune and inflammatory diseases, but its role in the CF has never been investigated. In this study, we examined the effect of DMF on CF-related cytokines expression, ROS measurements and CFTR channel function. We found that DMF reduced the inflammatory response to LPS stimulation in both CF and non-CF bronchial epithelial cells, both as co-treatment and therapy, and restored LPS-mediated decrease of Trikafta™-mediated CFTR function in CF cells bearing the most common mutation, c.1521_1523delCTT (F508del). DMF also inhibited the inflammatory response induced by IL-1β/H2O2 and IL-1β/TNFα, mimicking the inflammatory status of CF patients. Finally, we also demonstrated that DMF exhibited an anti-oxidant effect on CF cells after different inflammatory stimulations. Since DMF is an approved drug, it could be further investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF and improve the CFTR modulators efficacy.

scholarly journals Adult Patients Affected by Cystic Fibrosis in Therapy with Cystic Fibrosis Transmembrane Regulator Modulators and Lung Transplant: Renal Function, Metabolic and Nutritional Status

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Silvia Lai ◽  
Sandro Mazzaferro ◽  
Anna Paola Mitterhofer ◽  
Francesca Tinti ◽  
Enea Bonci ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Renal Function ◽  
Nutritional Status ◽  
Lung Transplant ◽  
Conservative Therapy ◽  
Control Group ◽  
Inflammatory Status ◽  
Significant Difference ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

Background. Cystic fibrosis (CF) is one of the most frequent genetic diseases. The discovery and implementation of new therapies prolonged the survival of CF patients in the last years. Evaluation of long-term complications could be useful to improve the outcome of these patients. Aim of the Study. To evaluate renal function, metabolic, nutritional, and inflammatory status in CF patients on cystic fibrosis transmembrane regulator (CFTR) modulators therapy as well as lung transplant recipients (LRs) and patients on conservative therapy (control group). Materials and Methods. We performed a prospective, longitudinal study on 69 CF patients. Clinical and laboratory parameters (metabolic and nutritional indices and inflammatory markers) were evaluated in all patients before starting CFTR therapy or transplant (T0) and after 3 years (T1). Results. We enrolled 69 CF patients (42 males). Patients were distributed into three groups. The average age was 35.01 ± 10.57 years for the control group (group 0), 32.47 ± 9.40 years for patients on CFTR modulators therapy (group 1), and 38.93 ± 7.14 years for LRs (group 2). At T1, we showed a significant difference among the three groups in terms of renal function indices: creatinine, eGFR, serum nitrogen as well as serum uric acid, sodium, and potassium ( p < 0.001 , p < 0.001 , p < 0.001 , p < 0.001 , p < 0.001 , and p < 0.001 , respectively), particularly in LRs patients. Significant differences were found in nutritional status parameters among the three groups: total protein, serum albumin, serum fibrinogen, serum transferrin, and white blood cell counts ( p < 0.001 , p = 0.037 , p = 0.04 , p = 0.003 , and p = 0.007 , respectively), particularly in LRs compared with other groups. Moreover, we found significant differences in metabolic profile (HbA1c, p = 0.026 ) and inflammatory status, with a significant difference in C-reactive protein values, neutrophil counts, and neutrophil-lymphocyte ratio (NLR) among the three groups ( p < 0.001 , p = 0.005 , and p = 0.026 , respectively). Conclusions. Our study showed a reduced renal function and poor nutritional status in LRs, along with worse metabolic control. Moreover, we showed a lower inflammatory status in patients on CFTR modulators therapy. Therefore, we suggest early and careful monitoring of renal function, metabolic, and nutritional parameters in CF patients, whether they are on conservative therapy, CFTR modulators therapy, and LRs patients.

scholarly journals Azithromycin Selectively Reduces Tumor Necrosis Factor Alpha Levels in Cystic Fibrosis Airway Epithelial Cells

2007 ◽  
Vol 51 (3) ◽  
pp. 975-981 ◽  
Author(s):  
Cristina Cigana ◽  
Baroukh Maurice Assael ◽  
Paola Melotti
Keyword(s):  
Cystic Fibrosis ◽  
Dna Binding ◽  
Tumor Necrosis ◽  
Airway Epithelial ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

ABSTRACT Azithromycin (AZM) ameliorates lung function in cystic fibrosis (CF) patients. This macrolide has been suggested to have anti-inflammatory properties as well as other effects potentially relevant for therapy of CF. In this study, we utilized three CF (IB3-1, 16HBE14o- AS3, and 2CFSMEo-) and two isogenic non-CF (C38 and 16HBE14o- S1) airway epithelial cell lines to investigate whether AZM could reduce tumor necrosis factor alpha (TNF-α) mRNA and protein levels by real-time quantitative PCR analysis and an enzyme-linked immunosorbent assay (ELISA), respectively. We studied the effects on the DNA binding of NF-κB and specificity protein 1 (Sp1) by an ELISA. Non-CF cells express significantly lower TNF-α mRNA and protein levels than an isogenic CF cell line. In CF cells, AZM treatment causes a 30% reduction of TNF-α mRNA levels (P < 0.05) and a 45% decrease in TNF-α secretion (P < 0.05), reaching approximately the levels of the untreated isogenic non-CF cells. In CF cells, NF-κB and Sp1 DNA binding activities were also significantly decreased (about 45 and 60%, respectively; P < 0.05) after AZM treatment. Josamycin, a macrolide lacking clinically described anti-inflammatory effects, was ineffective. Finally, AZM did not alter the mRNA expression levels of interleukin-6, a proinflammatory molecule not differentially expressed in CF and isogenic non-CF cells. The results of our study support the anti-inflammatory activities of this macrolide, since we show that AZM reduced the levels of TNF-α and propose inhibitions of NF-κB and Sp1 DNA binding as possible mechanisms of this effect.

scholarly journals Adiponectin Expression Is Modulated by Long-Term Physical Activity in Adult Patients Affected by Cystic Fibrosis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Rita Polito ◽  
Ersilia Nigro ◽  
Ausilia Elce ◽  
Maria Ludovica Monaco ◽  
Paola Iacotucci ◽  
...  
Keyword(s):  
Physical Activity ◽  
Cystic Fibrosis ◽  
Forced Expiratory Volume ◽  
Total Serum ◽  
C Reactive Protein ◽  
Protein Levels ◽  
Reactive Protein ◽  
Inflammatory Status ◽  
Inflammatory Processes

Cystic fibrosis (CF) is a genetic disease characterized by progressive decline of lung function and chronic airway inflammation. Adipose tissue, through adiponectin and leptin, exerts several effects on energy metabolism and inflammatory processes. This study evaluated the levels of adiponectin and leptin in adult healthy subjects, in patients with CF and their correlation with long-term physical activity. CF patients were divided into two groups (sedentary versus active) based on their regular physical activity over 3 years. Anthropometric and serum biochemical profiles of CF patients and controls were evaluated and compared. Total serum adiponectin and leptin levels were measured by ELISA; adiponectin oligomeric profiles were analysed by western blot. Adiponectin levels were significantly higher while leptin levels were lower in patients with CF than in healthy controls. Furthermore, adiponectin was significantly lower in active compared to sedentary CF (p=0.047), while leptin was slightly increased in active compared to sedentary CF. In addition, C-reactive protein levels were significantly lower in active than in sedentary CF patients (p=0.048). Interestingly, only in the active group adiponectin levels were inversely correlated with forced expiratory volume (FEV) 1% decrease/year and FEV1% decrease. Moreover, adiponectin levels negatively correlated with lipid profiles. Our findings indicated that regular, long-term physical activity in CF improves respiratory function, metabolism, and inflammation status. These improvements in patients’ conditions are associated with immunometabolic processes involving adiponectin, leptin, and C-reactive protein. Therefore, we propose that both adipokines may be a useful biomarker in the evaluation of metabolic and inflammatory status in patients with CF.

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