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Claus Bachert - One of the best experts on this subject based on the ideXlab platform.
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th2 cytokines orchestrate the secretion of muc5ac and muc5b in il 5 positive chronic rhinosinusitis with Nasal Polyps
Allergy, 2019Co-Authors: Yu Zhang, Claus Bachert, Gabriele Holtappels, Lara Derycke, Xiaoni Wang, L Zhang, Nan ZhangAbstract:Background Mucin over-secretion is a significant characteristic of chronic rhinosinusitis with Nasal Polyps (CRSwNP). This study aimed to investigate the relationship between Th2 cytokines and MUC5AC or MUC5B, and the mechanism of mucin over-secretion in the type-2 inflammatory endotype of CRSwNP. Methods Main Th-cell cytokines, associated mediators, and mucins were determined in the homogenates of Nasal Polyp samples from 21 CRSwNP patients and inferior turbinate samples from 8 controls, by ELISA or UniCAP system. Secretion of MUC5AC and MUC5B was measured in the supernatants of IL-5, IL-4, or IL-13 primed Nasal Polyp fragments. Co-localization of MUC5AC, MUC5B, and IL-4 receptor α (IL-4Rα) in CRSwNP and controls was evaluated by immunohistochemistry. Gene expression of IL-4Rα in the samples was measured by real-time reverse transcription-polymerase chain reaction. Results Baseline protein levels of the Th2-cytokines IL-4, IL-5, and IL-13, and mucins MUC5AC and MUC5B were significantly higher in the IL-5(+) CRSwNP group, compared to control and IL-5(-) CRSwNP groups. MUC5AC and MUC5B secretions were significantly increased in IL-4- or IL-13-primed, but not IL-5-primed fragments of Nasal Polyps. Immuno-stained serial sections demonstrated that IL-4Rα was widely expressed in the epithelium and submucosal glands in control and Nasal Polyp tissues. Gene expression of IL-4Rα was elevated in Nasal Polyp tissues, specifically in the IL-5(+) CRSwNP group. Conclusions In type-2 inflammatory Nasal Polyps, characterized by the tissue expression of IL-5, MUC5AC and MUC5B are overexpressed. Both IL-4 and IL-13 may upregulate mucin expression via IL-4Rα, which is also overexpressed in IL-5(+) CRSwNP.
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reduced need for surgery in severe Nasal Polyposis with mepolizumab randomized trial
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Philippe Gevaert, Claus Bachert, Valerie J. Lund, Ana R Sousa, Glenis K Scadding, Shuaib Nasser, Stephen R Durham, Marjolein E Cornet, Harsha H KariyawasamAbstract:Background Patients with eosinophilic Nasal Polyposis frequently require surgery, and recurrence rates are high. Objective We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral Nasal Polyposis. Methods This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent Nasal Polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic Nasal Polyp score and Nasal Polyposis severity visual analog scale (VAS) score. Secondary end points included change in Nasal Polyposis severity VAS score, endoscopic Nasal Polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, Nasal blockage, and sense of smell), patient-reported outcomes, and safety. Results One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in Nasal Polyposis severity VAS score, endoscopic Nasal Polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. Conclusion In patients with recurrent Nasal Polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.
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dupilumab improves all acq 5 individual items in patients with chronic rhinosinusitis with Nasal Polyposis crswnp and asthma results from a phase 2a trial
European Respiratory Journal, 2017Co-Authors: Peter Hellings, Claus Bachert, Joaquim Mullol, Leda Mannent, Robert M Naclerio, Daniel L Hamilos, Vijay N Joish, Nikhil Amin, Adeline Abbe, Christine TaniouAbstract:Introduction: Dupilumab (DPL), a fully human anti-interleukin (IL)-4 Rα monoclonal antibody, inhibits IL-4/IL-13 signalling, and improves endoscopic, radiographic, and clinical endpoints in patients (pts) with CRSwNP and asthma. Aims: Evaluate DPL effect on each of the 5 items of the Asthma Control Questionnaire (ACQ-5) in pts with CRSwNP and asthma. Methods: CRSwNP pts refractory to intraNasal corticosteroids were assigned to weekly doses of DPL 300 mg s.c. or placebo (PBO), with mometasone furoate Nasal spray. Asthma control was assessed using ACQ-5 at baseline and at Week 16. Results: Of 60 pts enrolled, 58.3% had asthma and used asthma medications. DPL showed clinically relevant improvements in total ACQ-5 (Table). Differences vs PBO were significant for each of the 5 items assessing asthma symptoms (shortness of breath; wheezing time; awake in the morning with symptoms), activity limitation and night-time awakenings (Table). Asthma-control improvement correlated with improvement in pt-reported outcomes (visual analogue scale; 22-item Sino-Nasal Outcome Test) and Nasal Polyp score. Injection-site reactions, headache, and nasopharyngitis were the most frequently reported adverse events with DPL. Conclusion: In CRSwNP pts with asthma, DPL significantly improved all asthma-related items. Improvement correlated with reduced Nasal Polyp burden.
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effect of subcutaneous dupilumab on Nasal Polyp burden in patients with chronic sinusitis and Nasal Polyposis a randomized clinical trial
JAMA, 2016Co-Authors: Philippe Gevaert, Claus Bachert, Joaquim Mullol, Leda Mannent, Robert M Naclerio, Berrylin J Ferguson, Peter Hellings, Lixia Jiao, Ling WangAbstract:Importance Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell–mediated diseases. Objective To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and Nasal Polyposis. Design, Setting, and Participants A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and Nasal Polyposis refractory to intraNasal corticosteroids with 16 weeks of follow-up. Interventions Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate Nasal spray for 16 weeks. Main Outcomes and Measures Change in endoscopic Nasal Polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. Results Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in Nasal Polyp score was −0.3 (95% CI, −1.0 to 0.4) with placebo and −1.9 (95% CI, −2.5 to −1.2) with dupilumab (LS mean difference, −1.6 [95% CI, −2.4 to −0.7]; P P P P Conclusions and Relevance Among adults with symptomatic chronic sinusitis and Nasal Polyposis refractory to intraNasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate Nasal spray compared with mometasone alone reduced endoscopic Nasal Polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. Trial Registration clinicaltrials.gov Identifier:NCT01920893
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immunoregulatory effects of bone marrow derived mesenchymal stem cells in the Nasal Polyp microenvironment
Mediators of Inflammation, 2014Co-Authors: Claudina Pereznovo, Rogerio Pezato, Danilo Cândido De Almeida, Thiago Freire Pinto Bezerra, Fernando De Sa Silva, Luis Carlos Gregorio, Richard Louis Voegels, Niels Olsen Saraiva Câmara, Claus BachertAbstract:Nasal Polyposis is a severe, chronic inflammatory condition of the paraNasal sinuses and is frequently associated with asthma and aspirin sensitivity. Mesenchymal stem cells exhibit a potent immunosuppressive effect in several inflammatory conditions, and their role in Nasal Polyposis remains little explored. Hence, we investigated whether bone marrow-derived mesenchymal stem cells could modulate cell phenotype in the Nasal Polyp milieu. After coculture with mesenchymal stem cells, the frequency of these inflammatory cells was found to decrease. Furthermore, mesenchymal stem cells promoted strong inhibition of CD4+ and CD8+ T cell proliferation, increased the frequency of CD4+CD25+Foxp3 T cells, and changed the global cytokine profile from an inflammatory to an anti-inflammatory response. We believe that mesenchymal stem cells may be a very useful adjunct for investigation of the inflammatory process in Nasal Polyposis, contributing to better understanding of the inflammatory course of this condition.
Heung Man Lee - One of the best experts on this subject based on the ideXlab platform.
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decreased expression of ccl17 in the disrupted Nasal Polyp epithelium and its regulation by il 4 and il 5
PLOS ONE, 2018Co-Authors: Byoungjae Kim, Il Ho Park, Sang Hag Lee, Heung Man Lee, Hyunji Lee, Doh Young Lee, Ha Kyun Kim, Cha Young Kang, Seung Hoon Lee, Seung Kuk BaekAbstract:Background In airway epithelium, thymus and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) are induced by defective epithelial barriers such as E-cadherin and attract the effector cells of Th2 immunity. However, the association between the epithelial barrier and CCL17 expression has not been studied in chronic rhinosinusitis with Nasal Polyp (CRSwNP). Thus, we aimed to evaluate the expression of CCL17 and its regulation by Th cytokines in Nasal Polyp (NP) epithelial cells. Methods The expression and distribution of CCL17, CCL22, E-cadherin and/or epidermal growth factor receptor (EGFR) were measured using real-time PCR, western blot, and immunohistochemistry and compared between normal ethmoid sinus epithelium and NP epithelium. In addition, the expression level of CCL17 was determined in cultured epithelial cells treated with IL-4, IL-5, IL-13, TNF-α, and IFN-γ. Results The expression of CCL17 was decreased in the NP epithelium compared to the epithelium of normal ethmoid sinus, whereas the expression of CCL22 was not decreased. E-cadherin was differentially distributed between the epithelium of normal ethmoid sinus and NP epithelium. EGFR was also decreased in NPs. Interestingly, the stimulation of cultured epithelial cells with Th2 cytokines, IL-4 and IL-5, resulted in an upregulation of CCL17 expression only in NP epithelial cells whereas the expression of CCL17 was increased in both normal epithelial cells and NP epithelial cells by Th1 cytokines. Conclusion Our results suggest that the decreased expression of CCL17 in defective NP epithelium may be closely connected to NP pathogenesis and can be differentially regulated by cytokines in the NP epithelium of patients with CRSwNP.
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effect of mecp2 on tgf β1 induced extracellular matrix production in Nasal Polyp derived fibroblasts
American Journal of Rhinology & Allergy, 2018Co-Authors: Jae Min Shin, Il Ho Park, Seoung Ae Lee, Soo Hyung Lee, Heung Man LeeAbstract:Purpose Methyl-CpG-binding protein 2 (MeCP2), known as a transcriptional regulator, has been suggested to play an important role in myofibroblast differentiation in the lung. The purpose of this study was to investigate the role of MeCP2 in transforming growth factor (TGF)- β1-induced myofibroblast differentiation and extracellular matrix (ECM) production in Nasal Polyp-derived fibroblasts (NPDFs). Methods To identify the expression of MeCP2 in Nasal Polyp tissues, immunohistochemistry staining and Western blot were performed. TGF- β1-induced NPDFs were treated with 5-azacytidine, a DNA methylation inhibitor, and the expression levels of α-SMA and fibronectin were determined by semiquantitative reverse transcription polymerase chain reaction, immunofluorescent staining, and Western blotting. The total soluble collagen was analyzed by the Sircol collagen assay. MeCP2 silenced by MeCP2-specific small interference ( si) RNA was verified by Western blot. Results The expression levels of MeCP2 increased in Nasal Polyp tissues compared to normal inferior turbinate tissues. 5-Azacytidine significantly inhibited the expression of α-SMA and fibronectin mRNA in a dose-dependent manner. In addition, 5-azacytidine suppressed collagen production and the expression of MeCP2 in the same manner. The expression levels of a-SMA and collagen production were significantly blocked by MeCP2 silencing in TGF- β1-induced NPDFs. Conclusions Our data suggest that MeCP2 plays an essential role in TGF- β1-induced myofibroblast differentiation and ECM production in NPDFs.
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vitamin d attenuates myofibroblast differentiation and extracellular matrix accumulation in Nasal Polyp derived fibroblasts through smad2 3 signaling pathway
Scientific Reports, 2017Co-Authors: Seoung Ae Lee, Il Ho Park, Jae Min Shin, Hyun Woo Yang, Heung Man LeeAbstract:To investigate the potential role of vitamin D (1,25(OH)2D3) in preventing the development of Nasal Polyps, we examined the effect of vitamin D on myofibroblast differentiation and extracellular matrix (ECM) production in TGF-β1-induced Nasal Polyp-derived fibroblasts (NPDFs) and elucidated the mechanisms underlying its inhibitory effect. 1,25(OH)2D3 significantly reduced expression levels of α-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-β1-induced NPDFs. 1,25(OH)2D3 suppressed activated Smad2/3 in time-course. Up-regulation of α-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-β1 was unaffected by 1,25(OH)2D3 in NPDFs after vitamin D receptor-specific siRNA transfection. We confirmed that the Smad2/3-specific inhibitor SIS3 inactivated Smad2/3 and reduced α-SMA and fibronectin expression. Furthermore, acetylation of histone H3 was compromised by 1,25(OH)2D3, leading to inhibition of collagen 1A1, collagen 1A2 and α-SMA gene expression. Treatment with 1,25(OH)2D3 also significantly suppressed TGF-β1-enhanced contractility and motility in a contraction assay and Transwell migration assay. Finally, 1,25(OH)2D3 had a similar effect in ex vivo organ cultures of Nasal Polyps. Taken together, our results suggest that 1,25(OH)2D3 might be an effective therapy for Nasal Polyps by reducing myofibroblast differentiation and ECM production mediated by Smad2/3-dependent TGF-β1 signaling pathways in NPDFs.
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pirfenidone inhibits transforming growth factor β1 induced extracellular matrix production in Nasal Polyp derived fibroblasts
American Journal of Rhinology & Allergy, 2015Co-Authors: Jae Min Shin, Il Ho Park, Joo Hoo Park, Heung Man LeeAbstract:PurposePirfenidone has been shown to have antifibrotic and anti-inflammatory effects in the lungs. The purpose of this study was to evaluate the inhibitory effects of pirfenidone on transforming growth factor (TGF)-β1-induced myofibroblast differentiation and extracellular matrix accumulation. We also determined the molecular mechanisms of pirfenidone in Nasal Polyp-derived fibroblasts (NPDF).MethodsNPDFs were isolated from Nasal Polyps from eight patients who had chronic rhinosinusitis with Nasal Polyp. Pirfenidone was used to treat TGF-β1-induced NPDFs. Cytotoxicity was evaluated by using a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Fibroblast migration was evaluated with scratch assays. Expression levels of α-smooth muscle actin (SMA), fibronectin, and phosphorylated Smad2/3 were determined by Western blot and/or reverse transcription-polymerase chain reaction and immunofluorescent staining. Total collagen production was analyzed with the Sircol collagen assay and contractile a...
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lipopolysaccharide induces pro inflammatory cytokines and mmp production via tlr4 in Nasal Polyp derived fibroblast and organ culture
PLOS ONE, 2014Co-Authors: Jungsun Cho, Il Ho Park, Ju Hyung Kang, Inhye Han, Heung Man LeeAbstract:Nasal Polyposis is characterized by persistent inflammation and remodeling in sinoNasal mucosa. Toll-like receptors (TLRs) play a role in the innate immune response to microbes in the sinoNasal cavity. The aim of this study was to evaluate whether Nasal Polyp-derived fibroblasts (NPDFs) and organ-cultured Nasal Polyps can synthesize pro-inflammatory cytokines and matrix metalloproteinases (MMPs) after exposure to lipopolysaccharide (LPS), a TLR4 agonist. NPDFs and organ-cultured Nasal Polyps were isolated from Nasal Polyps of 8 patients and exposed to LPS. The mRNA and protein expression levels of TLRs, cytokines, and MMPs were determined using a gene expression microarray, real-time RT-PCR, western blot analysis, enzyme-linked immunosorbent assay, and immunofluorescence staining. The enzymatic activities of MMPs were analyzed using collagen or gelatin zymography. The protein expression level of MMP-1 increased in Nasal Polyp tissues compared to inferior turbinate tissues. LPS induced mRNA expression of TLR4, IL-6, IL-8, and MMP-1 and activated MAPK signaling in NPDFs. LPS promoted the release of interleukin (IL)-6 through extracellular signal-related kinase (ERK) and IL-8 through ERK and c-Jun N-terminal kinases (JNK). Production of IL-6 and IL-8 was induced by PI3K/Akt signaling in LPS-stimulated NPDFs. LPS increased the transcript and protein expression levels of MMP-1 and induced collagenase activity of MMP-1 via ERK and p38, but did not induce gelatinase activity of MMP-2 and MMP-9. LPS from Rhodobacter sphaeroides (LPS-RS) inhibited the stimulatory effects of LPS in NPDFs as well as in organ culture of Nasal Polyp. LPS triggers immune response via TLR 4 and activates MAPK and PI3K/Akt signaling pathway, which is involved in remodeling of Nasal Polyps.
Il Ho Park - One of the best experts on this subject based on the ideXlab platform.
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decreased expression of ccl17 in the disrupted Nasal Polyp epithelium and its regulation by il 4 and il 5
PLOS ONE, 2018Co-Authors: Byoungjae Kim, Il Ho Park, Sang Hag Lee, Heung Man Lee, Hyunji Lee, Doh Young Lee, Ha Kyun Kim, Cha Young Kang, Seung Hoon Lee, Seung Kuk BaekAbstract:Background In airway epithelium, thymus and activation-regulated chemokine (CCL17) and macrophage-derived chemokine (CCL22) are induced by defective epithelial barriers such as E-cadherin and attract the effector cells of Th2 immunity. However, the association between the epithelial barrier and CCL17 expression has not been studied in chronic rhinosinusitis with Nasal Polyp (CRSwNP). Thus, we aimed to evaluate the expression of CCL17 and its regulation by Th cytokines in Nasal Polyp (NP) epithelial cells. Methods The expression and distribution of CCL17, CCL22, E-cadherin and/or epidermal growth factor receptor (EGFR) were measured using real-time PCR, western blot, and immunohistochemistry and compared between normal ethmoid sinus epithelium and NP epithelium. In addition, the expression level of CCL17 was determined in cultured epithelial cells treated with IL-4, IL-5, IL-13, TNF-α, and IFN-γ. Results The expression of CCL17 was decreased in the NP epithelium compared to the epithelium of normal ethmoid sinus, whereas the expression of CCL22 was not decreased. E-cadherin was differentially distributed between the epithelium of normal ethmoid sinus and NP epithelium. EGFR was also decreased in NPs. Interestingly, the stimulation of cultured epithelial cells with Th2 cytokines, IL-4 and IL-5, resulted in an upregulation of CCL17 expression only in NP epithelial cells whereas the expression of CCL17 was increased in both normal epithelial cells and NP epithelial cells by Th1 cytokines. Conclusion Our results suggest that the decreased expression of CCL17 in defective NP epithelium may be closely connected to NP pathogenesis and can be differentially regulated by cytokines in the NP epithelium of patients with CRSwNP.
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effect of mecp2 on tgf β1 induced extracellular matrix production in Nasal Polyp derived fibroblasts
American Journal of Rhinology & Allergy, 2018Co-Authors: Jae Min Shin, Il Ho Park, Seoung Ae Lee, Soo Hyung Lee, Heung Man LeeAbstract:Purpose Methyl-CpG-binding protein 2 (MeCP2), known as a transcriptional regulator, has been suggested to play an important role in myofibroblast differentiation in the lung. The purpose of this study was to investigate the role of MeCP2 in transforming growth factor (TGF)- β1-induced myofibroblast differentiation and extracellular matrix (ECM) production in Nasal Polyp-derived fibroblasts (NPDFs). Methods To identify the expression of MeCP2 in Nasal Polyp tissues, immunohistochemistry staining and Western blot were performed. TGF- β1-induced NPDFs were treated with 5-azacytidine, a DNA methylation inhibitor, and the expression levels of α-SMA and fibronectin were determined by semiquantitative reverse transcription polymerase chain reaction, immunofluorescent staining, and Western blotting. The total soluble collagen was analyzed by the Sircol collagen assay. MeCP2 silenced by MeCP2-specific small interference ( si) RNA was verified by Western blot. Results The expression levels of MeCP2 increased in Nasal Polyp tissues compared to normal inferior turbinate tissues. 5-Azacytidine significantly inhibited the expression of α-SMA and fibronectin mRNA in a dose-dependent manner. In addition, 5-azacytidine suppressed collagen production and the expression of MeCP2 in the same manner. The expression levels of a-SMA and collagen production were significantly blocked by MeCP2 silencing in TGF- β1-induced NPDFs. Conclusions Our data suggest that MeCP2 plays an essential role in TGF- β1-induced myofibroblast differentiation and ECM production in NPDFs.
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vitamin d attenuates myofibroblast differentiation and extracellular matrix accumulation in Nasal Polyp derived fibroblasts through smad2 3 signaling pathway
Scientific Reports, 2017Co-Authors: Seoung Ae Lee, Il Ho Park, Jae Min Shin, Hyun Woo Yang, Heung Man LeeAbstract:To investigate the potential role of vitamin D (1,25(OH)2D3) in preventing the development of Nasal Polyps, we examined the effect of vitamin D on myofibroblast differentiation and extracellular matrix (ECM) production in TGF-β1-induced Nasal Polyp-derived fibroblasts (NPDFs) and elucidated the mechanisms underlying its inhibitory effect. 1,25(OH)2D3 significantly reduced expression levels of α-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-β1-induced NPDFs. 1,25(OH)2D3 suppressed activated Smad2/3 in time-course. Up-regulation of α-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-β1 was unaffected by 1,25(OH)2D3 in NPDFs after vitamin D receptor-specific siRNA transfection. We confirmed that the Smad2/3-specific inhibitor SIS3 inactivated Smad2/3 and reduced α-SMA and fibronectin expression. Furthermore, acetylation of histone H3 was compromised by 1,25(OH)2D3, leading to inhibition of collagen 1A1, collagen 1A2 and α-SMA gene expression. Treatment with 1,25(OH)2D3 also significantly suppressed TGF-β1-enhanced contractility and motility in a contraction assay and Transwell migration assay. Finally, 1,25(OH)2D3 had a similar effect in ex vivo organ cultures of Nasal Polyps. Taken together, our results suggest that 1,25(OH)2D3 might be an effective therapy for Nasal Polyps by reducing myofibroblast differentiation and ECM production mediated by Smad2/3-dependent TGF-β1 signaling pathways in NPDFs.
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pirfenidone inhibits transforming growth factor β1 induced extracellular matrix production in Nasal Polyp derived fibroblasts
American Journal of Rhinology & Allergy, 2015Co-Authors: Jae Min Shin, Il Ho Park, Joo Hoo Park, Heung Man LeeAbstract:PurposePirfenidone has been shown to have antifibrotic and anti-inflammatory effects in the lungs. The purpose of this study was to evaluate the inhibitory effects of pirfenidone on transforming growth factor (TGF)-β1-induced myofibroblast differentiation and extracellular matrix accumulation. We also determined the molecular mechanisms of pirfenidone in Nasal Polyp-derived fibroblasts (NPDF).MethodsNPDFs were isolated from Nasal Polyps from eight patients who had chronic rhinosinusitis with Nasal Polyp. Pirfenidone was used to treat TGF-β1-induced NPDFs. Cytotoxicity was evaluated by using a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Fibroblast migration was evaluated with scratch assays. Expression levels of α-smooth muscle actin (SMA), fibronectin, and phosphorylated Smad2/3 were determined by Western blot and/or reverse transcription-polymerase chain reaction and immunofluorescent staining. Total collagen production was analyzed with the Sircol collagen assay and contractile a...
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lipopolysaccharide induces pro inflammatory cytokines and mmp production via tlr4 in Nasal Polyp derived fibroblast and organ culture
PLOS ONE, 2014Co-Authors: Jungsun Cho, Il Ho Park, Ju Hyung Kang, Inhye Han, Heung Man LeeAbstract:Nasal Polyposis is characterized by persistent inflammation and remodeling in sinoNasal mucosa. Toll-like receptors (TLRs) play a role in the innate immune response to microbes in the sinoNasal cavity. The aim of this study was to evaluate whether Nasal Polyp-derived fibroblasts (NPDFs) and organ-cultured Nasal Polyps can synthesize pro-inflammatory cytokines and matrix metalloproteinases (MMPs) after exposure to lipopolysaccharide (LPS), a TLR4 agonist. NPDFs and organ-cultured Nasal Polyps were isolated from Nasal Polyps of 8 patients and exposed to LPS. The mRNA and protein expression levels of TLRs, cytokines, and MMPs were determined using a gene expression microarray, real-time RT-PCR, western blot analysis, enzyme-linked immunosorbent assay, and immunofluorescence staining. The enzymatic activities of MMPs were analyzed using collagen or gelatin zymography. The protein expression level of MMP-1 increased in Nasal Polyp tissues compared to inferior turbinate tissues. LPS induced mRNA expression of TLR4, IL-6, IL-8, and MMP-1 and activated MAPK signaling in NPDFs. LPS promoted the release of interleukin (IL)-6 through extracellular signal-related kinase (ERK) and IL-8 through ERK and c-Jun N-terminal kinases (JNK). Production of IL-6 and IL-8 was induced by PI3K/Akt signaling in LPS-stimulated NPDFs. LPS increased the transcript and protein expression levels of MMP-1 and induced collagenase activity of MMP-1 via ERK and p38, but did not induce gelatinase activity of MMP-2 and MMP-9. LPS from Rhodobacter sphaeroides (LPS-RS) inhibited the stimulatory effects of LPS in NPDFs as well as in organ culture of Nasal Polyp. LPS triggers immune response via TLR 4 and activates MAPK and PI3K/Akt signaling pathway, which is involved in remodeling of Nasal Polyps.
Nan Zhang - One of the best experts on this subject based on the ideXlab platform.
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th2 cytokines orchestrate the secretion of muc5ac and muc5b in il 5 positive chronic rhinosinusitis with Nasal Polyps
Allergy, 2019Co-Authors: Yu Zhang, Claus Bachert, Gabriele Holtappels, Lara Derycke, Xiaoni Wang, L Zhang, Nan ZhangAbstract:Background Mucin over-secretion is a significant characteristic of chronic rhinosinusitis with Nasal Polyps (CRSwNP). This study aimed to investigate the relationship between Th2 cytokines and MUC5AC or MUC5B, and the mechanism of mucin over-secretion in the type-2 inflammatory endotype of CRSwNP. Methods Main Th-cell cytokines, associated mediators, and mucins were determined in the homogenates of Nasal Polyp samples from 21 CRSwNP patients and inferior turbinate samples from 8 controls, by ELISA or UniCAP system. Secretion of MUC5AC and MUC5B was measured in the supernatants of IL-5, IL-4, or IL-13 primed Nasal Polyp fragments. Co-localization of MUC5AC, MUC5B, and IL-4 receptor α (IL-4Rα) in CRSwNP and controls was evaluated by immunohistochemistry. Gene expression of IL-4Rα in the samples was measured by real-time reverse transcription-polymerase chain reaction. Results Baseline protein levels of the Th2-cytokines IL-4, IL-5, and IL-13, and mucins MUC5AC and MUC5B were significantly higher in the IL-5(+) CRSwNP group, compared to control and IL-5(-) CRSwNP groups. MUC5AC and MUC5B secretions were significantly increased in IL-4- or IL-13-primed, but not IL-5-primed fragments of Nasal Polyps. Immuno-stained serial sections demonstrated that IL-4Rα was widely expressed in the epithelium and submucosal glands in control and Nasal Polyp tissues. Gene expression of IL-4Rα was elevated in Nasal Polyp tissues, specifically in the IL-5(+) CRSwNP group. Conclusions In type-2 inflammatory Nasal Polyps, characterized by the tissue expression of IL-5, MUC5AC and MUC5B are overexpressed. Both IL-4 and IL-13 may upregulate mucin expression via IL-4Rα, which is also overexpressed in IL-5(+) CRSwNP.
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characterization of human and staphylococcus aureus proteins in respiratory mucosa by in vivo and immunoproteomics
Journal of Proteomics, 2017Co-Authors: Frank Schmidt, Gabriele Holtappels, Tanja C Meyer, Nandakumar Sundaramoorthy, Stephan Michalik, Kristin Surmann, Maren Depke, Vishnu M Dhople, Manuela Gesell Salazar, Nan ZhangAbstract:Abstract Staphylococcus aureus is a Gram-positive opportunistic bacterium which can be found as a commensal in the nares of about 50% of the human population. Besides asymptomatic carriage, S. aureus has also been found to colonize Nasal Polyps, a subform of chronic rhinosinusitis, in 60 to 100% of cases, and even reside intracellularly in Nasal Polyp tissue. The aim of this study was to shed light on the behavior of S. aureus in the human airways by analyzing S. aureus -specific proteins in Nasal Polyp tissue from patients with chronic rhinosinusitis and to characterize the immunogenic potential of the identified (mainly secreted) proteins. As a result, in total > 600 S. aureus proteins were identified by high resolution mass spectrometry or multiple reaction monitoring. Of those roughly 180 are typically localized in the membrane, surface exposed or secreted. For 115 S. aureus proteins, partially also detected in vivo by mass spectrometry, IgA- and IgG-specific antibody signals were profiled. Strong antibody signals were predominantly found for surface expose or secreted proteins. Significance In this study, we used high resolution mass spectrometry to identify S. aureus proteins directly in infected Nasal Polyp tissue. We discovered bacterial proteins involved in invasion of tissue, virulence, bacterial signal transduction or acquisition of nutrients. Some of the detected superantigens and Spls are known to provoke secretion of a broad spectrum of cytokines. Therefore, our manuscript contains new information about the invasion of S. aureus in Nasal Polyp tissue and its protein-specific immunogenicity.
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herpes simplex virus type 1 infection facilitates invasion of staphylococcus aureus into the Nasal mucosa and Nasal Polyp tissue
PLOS ONE, 2012Co-Authors: Gabriele Holtappels, Xiangdong Wang, Nan Zhang, Sarah Glorieux, Mario Vaneechoutte, Olga Krysko, Luo Zhang, Demin Han, Hans NauwynckAbstract:Background Staphylococcus aureus (S. aureus) plays an important role in the pathogenesis of severe chronic airway disease, such as Nasal Polyps. However the mechanisms underlying the initiation of damage and/or invasion of the Nasal mucosa by S. aureus are not clearly understood. The aim of this study was to investigate the interaction between S. aureus and herpes simplex virus type 1 (HSV1) in the invasion of the Nasal mucosa and Nasal Polyp tissue.
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il 17a as a regulator of neutrophil survival in Nasal Polyp disease of patients with and without cystic fibrosis
Journal of Cystic Fibrosis, 2012Co-Authors: Lara Derycke, Nan Zhang, Gabriele Holtappels, Tineke Dutre, Claus BachertAbstract:Abstract Nasal Polyps in adults are characterized by a chronic inflammation of the upper airways and by the preferential activation of Th2 cells. In contrast, IL-17 producing Th17 cells dominate the inflammation in Nasal Polyps of cystic fibrosis (CF) patients. Method IL-17A, IL-5, IL-6, IL-8, IL-1β, ECP, MCP-1 and myeloperoxidase expression was determined in tissue homogenates of Nasal Polyps of non-CF and CF patients and controls. The cellular source of IL-17A was determined by immuno-histochemistry and FACS analysis. The functional role of IL-17A in the survival of neutrophils from CF and non-CF patients was tested. Results A significant upregulation of IL-17A and myeloperoxidase could be observed in Nasal Polyps from CF-patients. The cellular sources of IL-17A in Nasal Polyps were mainly T-lymphocytes. IL-17A was able to modulate the survival of neutrophils in Nasal Polyps from non-CF patients; however the survival of neutrophils in CF patients was independent of IL-17A. Conclusion The present study shows that IL-17A has an impact on neutrophil survival in adult Nasal Polyp disease, but not in Nasal Polyps from CF patients.
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crth2 mediates the activation of human th2 cells in response to pgd 2 released from ige anti ige treated Nasal Polyp tissue
Allergy, 2010Co-Authors: Claudina Pereznovo, Claus Bachert, Gabriele Holtappels, Nan Zhang, Shân L Vinall, Luzheng Xue, Roy PettipherAbstract:BACKGROUND: Mast cells release mediators upon stimulation that contribute to the pathogenesis of chronic airway disease, including the recruitment and activation of Th2 lymphocytes. The objective was to determine the involvement of prostaglandin D(2) (PGD(2)) and its receptors in the chemotaxis of Th2 cells, using Nasal Polyp tissue. METHODS: Tissue explants from ten patients with Nasal Polyposis were incubated with RPMI alone or RPMI containing IgE/anti-IgE for 30 min. Some samples were treated with diclofenac to inhibit the production of PGD(2). Supernatants were assayed for PGD(2) content and for their ability to promote human Th2 cell chemotaxis in the presence and absence of a CRTH2 antagonist. Transcript levels of D protanoid receptor type 1 (DP(1)), chemoattractant receptor-homologous receptor expressed on Th2 cells (CRTH2) and PGD(2) synthase were analysed by real time PCR. RESULTS: Increased release of PGD(2) by Nasal Polyp tissue treated with IgE/anti-IgE was significantly inhibited by preincubation of the tissue with diclofenac. Transcript levels of PGD(2) synthase, DP(1) and CRTH2 receptors increased after stimulation with IgE/anti-IgE. Supernatants from IgE/anti-IgE-stimulated Nasal Polyp tissue caused significantly increased chemotaxis of Th2 cells. The levels of PGD(2) produced and the degree of Th2 cell chemotaxis were highly correlated. Diclofenac inhibited the production of Th2 cell chemotactic activity, and the chemotactic effect of the supernatant on Th2 cells was inhibited by the CRTH2 antagonist ramatroban. CONCLUSION: These data suggest that in immunologically activated Nasal Polyp tissue, PGD(2) produced by mast cells promotes the migration of Th2 cells through a CRTH2 dependent mechanism.
Gabriele Holtappels - One of the best experts on this subject based on the ideXlab platform.
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th2 cytokines orchestrate the secretion of muc5ac and muc5b in il 5 positive chronic rhinosinusitis with Nasal Polyps
Allergy, 2019Co-Authors: Yu Zhang, Claus Bachert, Gabriele Holtappels, Lara Derycke, Xiaoni Wang, L Zhang, Nan ZhangAbstract:Background Mucin over-secretion is a significant characteristic of chronic rhinosinusitis with Nasal Polyps (CRSwNP). This study aimed to investigate the relationship between Th2 cytokines and MUC5AC or MUC5B, and the mechanism of mucin over-secretion in the type-2 inflammatory endotype of CRSwNP. Methods Main Th-cell cytokines, associated mediators, and mucins were determined in the homogenates of Nasal Polyp samples from 21 CRSwNP patients and inferior turbinate samples from 8 controls, by ELISA or UniCAP system. Secretion of MUC5AC and MUC5B was measured in the supernatants of IL-5, IL-4, or IL-13 primed Nasal Polyp fragments. Co-localization of MUC5AC, MUC5B, and IL-4 receptor α (IL-4Rα) in CRSwNP and controls was evaluated by immunohistochemistry. Gene expression of IL-4Rα in the samples was measured by real-time reverse transcription-polymerase chain reaction. Results Baseline protein levels of the Th2-cytokines IL-4, IL-5, and IL-13, and mucins MUC5AC and MUC5B were significantly higher in the IL-5(+) CRSwNP group, compared to control and IL-5(-) CRSwNP groups. MUC5AC and MUC5B secretions were significantly increased in IL-4- or IL-13-primed, but not IL-5-primed fragments of Nasal Polyps. Immuno-stained serial sections demonstrated that IL-4Rα was widely expressed in the epithelium and submucosal glands in control and Nasal Polyp tissues. Gene expression of IL-4Rα was elevated in Nasal Polyp tissues, specifically in the IL-5(+) CRSwNP group. Conclusions In type-2 inflammatory Nasal Polyps, characterized by the tissue expression of IL-5, MUC5AC and MUC5B are overexpressed. Both IL-4 and IL-13 may upregulate mucin expression via IL-4Rα, which is also overexpressed in IL-5(+) CRSwNP.
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characterization of human and staphylococcus aureus proteins in respiratory mucosa by in vivo and immunoproteomics
Journal of Proteomics, 2017Co-Authors: Frank Schmidt, Gabriele Holtappels, Tanja C Meyer, Nandakumar Sundaramoorthy, Stephan Michalik, Kristin Surmann, Maren Depke, Vishnu M Dhople, Manuela Gesell Salazar, Nan ZhangAbstract:Abstract Staphylococcus aureus is a Gram-positive opportunistic bacterium which can be found as a commensal in the nares of about 50% of the human population. Besides asymptomatic carriage, S. aureus has also been found to colonize Nasal Polyps, a subform of chronic rhinosinusitis, in 60 to 100% of cases, and even reside intracellularly in Nasal Polyp tissue. The aim of this study was to shed light on the behavior of S. aureus in the human airways by analyzing S. aureus -specific proteins in Nasal Polyp tissue from patients with chronic rhinosinusitis and to characterize the immunogenic potential of the identified (mainly secreted) proteins. As a result, in total > 600 S. aureus proteins were identified by high resolution mass spectrometry or multiple reaction monitoring. Of those roughly 180 are typically localized in the membrane, surface exposed or secreted. For 115 S. aureus proteins, partially also detected in vivo by mass spectrometry, IgA- and IgG-specific antibody signals were profiled. Strong antibody signals were predominantly found for surface expose or secreted proteins. Significance In this study, we used high resolution mass spectrometry to identify S. aureus proteins directly in infected Nasal Polyp tissue. We discovered bacterial proteins involved in invasion of tissue, virulence, bacterial signal transduction or acquisition of nutrients. Some of the detected superantigens and Spls are known to provoke secretion of a broad spectrum of cytokines. Therefore, our manuscript contains new information about the invasion of S. aureus in Nasal Polyp tissue and its protein-specific immunogenicity.
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herpes simplex virus type 1 infection facilitates invasion of staphylococcus aureus into the Nasal mucosa and Nasal Polyp tissue
PLOS ONE, 2012Co-Authors: Gabriele Holtappels, Xiangdong Wang, Nan Zhang, Sarah Glorieux, Mario Vaneechoutte, Olga Krysko, Luo Zhang, Demin Han, Hans NauwynckAbstract:Background Staphylococcus aureus (S. aureus) plays an important role in the pathogenesis of severe chronic airway disease, such as Nasal Polyps. However the mechanisms underlying the initiation of damage and/or invasion of the Nasal mucosa by S. aureus are not clearly understood. The aim of this study was to investigate the interaction between S. aureus and herpes simplex virus type 1 (HSV1) in the invasion of the Nasal mucosa and Nasal Polyp tissue.
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il 17a as a regulator of neutrophil survival in Nasal Polyp disease of patients with and without cystic fibrosis
Journal of Cystic Fibrosis, 2012Co-Authors: Lara Derycke, Nan Zhang, Gabriele Holtappels, Tineke Dutre, Claus BachertAbstract:Abstract Nasal Polyps in adults are characterized by a chronic inflammation of the upper airways and by the preferential activation of Th2 cells. In contrast, IL-17 producing Th17 cells dominate the inflammation in Nasal Polyps of cystic fibrosis (CF) patients. Method IL-17A, IL-5, IL-6, IL-8, IL-1β, ECP, MCP-1 and myeloperoxidase expression was determined in tissue homogenates of Nasal Polyps of non-CF and CF patients and controls. The cellular source of IL-17A was determined by immuno-histochemistry and FACS analysis. The functional role of IL-17A in the survival of neutrophils from CF and non-CF patients was tested. Results A significant upregulation of IL-17A and myeloperoxidase could be observed in Nasal Polyps from CF-patients. The cellular sources of IL-17A in Nasal Polyps were mainly T-lymphocytes. IL-17A was able to modulate the survival of neutrophils in Nasal Polyps from non-CF patients; however the survival of neutrophils in CF patients was independent of IL-17A. Conclusion The present study shows that IL-17A has an impact on neutrophil survival in adult Nasal Polyp disease, but not in Nasal Polyps from CF patients.
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crth2 mediates the activation of human th2 cells in response to pgd 2 released from ige anti ige treated Nasal Polyp tissue
Allergy, 2010Co-Authors: Claudina Pereznovo, Claus Bachert, Gabriele Holtappels, Nan Zhang, Shân L Vinall, Luzheng Xue, Roy PettipherAbstract:BACKGROUND: Mast cells release mediators upon stimulation that contribute to the pathogenesis of chronic airway disease, including the recruitment and activation of Th2 lymphocytes. The objective was to determine the involvement of prostaglandin D(2) (PGD(2)) and its receptors in the chemotaxis of Th2 cells, using Nasal Polyp tissue. METHODS: Tissue explants from ten patients with Nasal Polyposis were incubated with RPMI alone or RPMI containing IgE/anti-IgE for 30 min. Some samples were treated with diclofenac to inhibit the production of PGD(2). Supernatants were assayed for PGD(2) content and for their ability to promote human Th2 cell chemotaxis in the presence and absence of a CRTH2 antagonist. Transcript levels of D protanoid receptor type 1 (DP(1)), chemoattractant receptor-homologous receptor expressed on Th2 cells (CRTH2) and PGD(2) synthase were analysed by real time PCR. RESULTS: Increased release of PGD(2) by Nasal Polyp tissue treated with IgE/anti-IgE was significantly inhibited by preincubation of the tissue with diclofenac. Transcript levels of PGD(2) synthase, DP(1) and CRTH2 receptors increased after stimulation with IgE/anti-IgE. Supernatants from IgE/anti-IgE-stimulated Nasal Polyp tissue caused significantly increased chemotaxis of Th2 cells. The levels of PGD(2) produced and the degree of Th2 cell chemotaxis were highly correlated. Diclofenac inhibited the production of Th2 cell chemotactic activity, and the chemotactic effect of the supernatant on Th2 cells was inhibited by the CRTH2 antagonist ramatroban. CONCLUSION: These data suggest that in immunologically activated Nasal Polyp tissue, PGD(2) produced by mast cells promotes the migration of Th2 cells through a CRTH2 dependent mechanism.
