Vimentin Expression in Nasal Mucosa of Patients with Exacerbated Chronic Rhinosinusitis Without Nasal Polyps

Abstract Objective. The aim of the study was to evaluate vimentin expression in inflamed nasal mucosa of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) and serum levels of matrix metalloproteinase-9 (MMP-9). Material and Methods. We measured concentrations of MMP-9 in blood serum of twenty patients with CRSsNP using ELISA and compared them with the control group composed of twenty healthy subjects. Vimentin expression in nasal mucosa was studied by an immunohistochemical method. Results. Blood serum levels of MMP-9 were found to be elevated in patients with CRSsNP. The disease was also associated with the upregulation of vimentin expression both in the lamina propria and nasal epithelial layer. Conclusion. CRSsNP is accompanied by a higher number of vimentin-expressing cells in the nasal epithelium, which may indicate their epithelial-to-mesenchymal transition (EMT). We speculate that MMP-9 may contribute to the increased rate of EMT of nasal epithelial cells in CRSsNP.

Download Full-text

Pharmacologic Targeting of BET Proteins Attenuates Hyperuricemic Nephropathy in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.636154 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chongxiang Xiong ◽

Jin Deng ◽

Xin Wang ◽

Xiaofei Shao ◽

Qin Zhou ◽

...

Keyword(s):

Uric Acid ◽

Epithelial To Mesenchymal Transition ◽

Organic Anion ◽

Mesenchymal Cell ◽

Serum Levels ◽

Organic Anion Transporter ◽

Vimentin Expression ◽

Mesenchymal Transition ◽

Expression Levels ◽

Anion Transporter

Hyperuricemia is an independent risk factor for renal damage and promotes the progression of chronic kidney disease. In this study, we investigated the effect of I-BET151, a small-molecule inhibitor targeting the bromodomain and extraterminal (BET) proteins, on the development of hyperuricemic nephropathy (HN), and the mechanisms involved. Expression levels of bromodomain-containing protein 2 and 4, but not 3 were increased in the kidney of rats with HN; administration of I-BET151 effectively prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis as indicated by reduced activation of renal interstitial fibroblasts and expression of fibronectin and collagen I in HN rats. Mechanistic studies show that I-BET151 treatment inhibited transition of renal epithelial cells to a mesenchymal cell type as evidenced by preservation of E-cadherin and reduction of vimentin expression. This was coincident with reduced expression of TGF-β1 and dephosphorylation of Smad3 and ERK1/2. I-BET151 was also effective in inhibiting phosphorylation of NF-κB, expression of multiple cytokines and chemokines, and infiltration of macrophages to the injured kidney. Although there were increased serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and decreased expression of renal organic anion transporter 1 and 3 that promote urate excretion in the model of HN, and reduced expression levels of urine uric acid, I-BET151 treatment did not affect these responses. Collectively, our results indicate that I-BET151 alleviates HN by inhibiting epithelial to mesenchymal transition and inflammation in association with blockade of TGF-β, ERK1/2 and NF-κB signaling.

Download Full-text

Deficit in Adipose Differentiation in Mesenchymal Stem Cells Derived from Chronic Rhinosinusitis Nasal Polyps Compared to Nasal Mucosal Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms21239214 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9214

Author(s):

Emanuela Chiarella ◽

Nicola Lombardo ◽

Nadia Lobello ◽

Giovanna Lucia Piazzetta ◽

Helen Linda Morrone ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Chronic Rhinosinusitis ◽

Nasal Mucosa ◽

Nasal Polyps ◽

Epithelial Mesenchymal Transition ◽

Nasal Congestion ◽

Normal Mucosa ◽

Molecular Response ◽

Mesenchymal Transition

Chronic rhinosinusitis of the nasal mucosa is an inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia, and in some cases, it can result in the development of nasal polyposis. Nasal polyps are benign lobular-shaped growths that project in the nasal cavities; they originate from inflammation in the paranasal mucous membrane and are associated with a high expression of interleukins (IL)-4, IL-5, IL-13, and IgE. Polyps derive from the epithelial–mesenchymal transition of the nasal epithelium resulting in a nasal tissue remodeling. Nasal polyps from three patients with chronic rhinosinusitis as well as control non-polyp nasal mucosa were used to isolate and cultivate mesenchymal stem cells characterized as CD73+, CD90+, CD105+/CD14−, CD34−, and CD45−. Mesenchymal stem cells (MSCs) cultures were induced to differentiate toward adipocytes, where lipid droplets and adipocyte genes PPARγ2, ADIPO-Q, and FABP4 were observed in control non-polyp nasal mucosa-derived mesenchymal cells but were scarcely present in the cultures derived from the nasal polyps, where apoptosis was evident. The modulation of the response to adipogenic stimulus in polyps represents a change in the molecular response that controls the cascade required for differentiation as well as possible means to specifically target these cells, sparing the normal mucosa of the nasal sinuses.

Download Full-text

Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp

Thorax ◽

10.1136/thoraxjnl-2019-213916 ◽

2020 ◽

Vol 75 (11) ◽

pp. 982-993 ◽

Cited By ~ 1

Author(s):

Jun-Sang Bae ◽

Gwanghui Ryu ◽

Ji Hye Kim ◽

Eun Hee Kim ◽

Yun Hee Rhee ◽

...

Keyword(s):

Wnt Signaling ◽

Chronic Rhinosinusitis ◽

Nasal Polyp ◽

Epithelial To Mesenchymal Transition ◽

Smooth Muscle Actin ◽

Positive Control ◽

Control Group ◽

Mrna Levels ◽

Mesenchymal Transition ◽

E Cadherin

BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear β-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP.ConclusionWnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.

Download Full-text

Eosinophils Correlate with Epithelial-Mesenchymal Transition in Chronic Rhinosinusitis with Nasal Polyps

ORL ◽

10.1159/000516847 ◽

2021 ◽

pp. 1-11

Author(s):

Mingjie Wang ◽

Yan Sun ◽

Cheng Li ◽

Jing Qu ◽

Bing Zhou

Keyword(s):

Epithelial Cells ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Epithelial Mesenchymal Transition ◽

Airway Remodeling ◽

Eosinophil Infiltration ◽

Control Group ◽

Epithelial Tissue ◽

Mesenchymal Transition ◽

Eosinophilic Chronic Rhinosinusitis

Introduction: Chronic inflammation and tissue remodeling always occur together in chronic rhinosinusitis (CRS). Epithelial-mesenchymal transition (EMT) plays a critical role in airway remodeling. Objective: Changes of epithelial cells in sinus mucosa in different subtypes of CRS, especially in eosinophilic chronic rhinosinusitis with nasal polyps, and the role of EMT and eosinophils (EOS) in airway remodeling are still unknown. Methods: We included 85 patients in this study. They were divided into 4 groups: a normal control (NC) group, a chronic rhinosinusitis without nasal polyps (CRSsNP) group, an eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) group, and a noneosinophilic chronic rhinosinusitis with nasal polyps (non-ECRSwNP) group. Clinical data were all collected and analyzed. Standard hematoxylin and eosin staining, immunohistochemical staining, and 2-color immunofluorescence staining were performed. Biomarkers of EMT, epithelial cadherin, and vimentin were labeled. The immunohistochemistry results of each group were counted and statistically analyzed. Results and Conclusion: E-cadherin was downregulated, and vimentin was upregulated in epithelial tissue from the ECRSwNP group, compared with that from the control group and the other groups. The number of vimentin-expressing epithelial cells correlated with sinus CT imaging Lund-Mackay scores (r = 0.560, p < 0.001). Moreover, expression levels of vimentin in the epithelium were associated with numbers of infiltrating EOS in tissues (r = 0.710, p < 0.001) and the peripheral blood EOS ratio (r = 0.594, p < 0.001). EMT occurred in patients with CRSwNP, especially in those with ECRSwNP. Epithelial reprogramming correlates with eosinophil infiltration and disease severity. Eosinophils contributed to impairment of epithelial function and promoted EMT in CRSwNP.

Download Full-text

TGF-β1 induces epithelial-to-mesenchymal transition in chronic rhinosinusitis with nasal polyps through microRNA-182

Asian Pacific Journal of Allergy and Immunology ◽

10.12932/ap-040921-1224 ◽

2022 ◽

Keyword(s):

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Tgf Β1

Download Full-text

Expression of Transcript Variants of PTGS1 and PTGS2 Genes among Patients with Chronic Rhinosinusitis with Nasal Polyps

Diagnostics ◽

10.3390/diagnostics11010135 ◽

2021 ◽

Vol 11 (1) ◽

pp. 135

Author(s):

Wioletta Pietruszewska ◽

Wojciech Fendler ◽

Marta Podwysocka ◽

Adam J. Białas ◽

Piotr Kuna ◽

...

Keyword(s):

Healthy Volunteers ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Direct Sequencing ◽

Adult Patients ◽

Control Group ◽

Reliable Test ◽

Aggressive Disease ◽

Transcript Variants

To date, there has been no reliable test to identify unfavorable course of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), especially in aspirin intolerant patients. The research aimed to analyze the expression of transcript variants of PTGS1 and PTGS2 genes in the pathobiology of the disease. The study was performed on 409 adult patients: 206 CRSwNP patients including 44 (21.36%) aspirin intolerant patients and 203 healthy volunteers in the control group. Transcript variants of the PTGS1 and PTGS2 genes named as follows: COX1.1 for NM_000962, COX1.2 for NM_080591, COX1.3 for NM_001271165.1, COX1.4 for NM_001271368.1, COX1.5 for NM_001271166.1, COX2.1 for NM_000963.3, COX2.2 for AY_151286 and COX2.3 for BQ_722004 were confirmed using direct sequencing and quantified using targeted qPCR. The coexistence of all examined transcript variants in the study and the control group and significant differences between both were found. In aspirin sensitive patients, the levels of COX1.2, COX1.3, COX1.4 and COX1.5 isoforms were higher compared to aspirin-tolerant patients. The severity of symptoms was bigger in patients with higher expressions of variants: COX1.1 (R with dCt = −0.134; p = 0.0490), COX1.3 (R = −0.1429; p = 0.0400) and COX1.5 (Rs = −0.1499; p = 0.032). The expression of COX1.1 (Rs = −0.098; p = 0.049) and COX1.5 (Rs = −0.141; p = 0.043) isoforms increased with polyposis advancement in endoscopy. With the CT extent of sinuses opacification, COX1.1 isoform also significantly increased (Rs = −0.163; p = 0.020). The isoforms COX1.3, COX1.4, COX1.5 and COX2.1 may promote milder CRSwNP course. On the contrary, the variants COX1.1, COX1.2 and COX2.2 may be involved in a more aggressive disease.

Download Full-text

Characterization of Cytokines and Proliferation Marker Ki67 in Chronic Rhinosinusitis with Nasal Polyps: A Pilot Study

Medicina ◽

10.3390/medicina57060607 ◽

2021 ◽

Vol 57 (6) ◽

pp. 607

Author(s):

Rudolfs Janis Viksne ◽

Gunta Sumeraga ◽

Mara Pilmane

Keyword(s):

Connective Tissue ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Cellular Proliferation ◽

Rank Correlation ◽

Control Group ◽

Relative Distribution ◽

Proliferation Marker ◽

Ki 67 ◽

Stimulation Of

Background and Objectives: Chronic rhinosinusitis (CRS) is a condition that affects as much as 10.9% of the population and, along with presence of nasal polyps, is associated with significant morbidity and decreased quality of life. Studies on molecular pathways that have been activated in nasal polyp tissue are mainly based on cytokine concentration detection. Therefore, our aim is to investigate the complex appearance, relative distribution and interlinks of IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki 67 in chronic rhinosinusitis with nasal polyps (CRSwNP) affected human nasal mucosa. Materials and Methods: Samples of nasal polyps were obtained from 12 patients with previously diagnosed CRSwNP and no prior surgery. Control group consisted of samples from 17 otherwise healthy individuals with isolated nasal septum deviation. Tissues were stained for IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki67 immunohistochemically. Non-parametric statistic, Mann–Whitney U test and Spearman’s rank correlation coefficient were used. Results: All factors, except connective tissue cytokine IL-10 and proliferation marker Ki-67, had increased presence in connective tissue and decreased presence in epithelium of nasal polyps when compared to controls. Very strong and strong positive correlations between factors were observed. Conclusions: Decreased appearance of IL-1α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 positive structures in the nasal epithelium with selective increase of IL-1α and IL-12 in nasal subepithelial connective tissue characterize the cytokine endotype with dysfunctional epithelial barrier and local stimulation of immune response in the connective tissue in case of chronic rhinosinusitis with polyps. Decrease of IL-6 in both—epithelium and connective tissue with strong correlation between it and IL-7 and IL-10 in connective tissue suggests significant stimulation of this regulatory cytokine and, possibly, the important role in pathogenesis of the development in nasal polyps. Correlations between Ki67 and cytokines indicate possible involvement of IL-4, IL-7 and IL-12 in regulation of cellular proliferation.

Download Full-text

Association between obesity and chronic rhinosinusitis with nasal polyps: a national population-based study

BMJ Open ◽

10.1136/bmjopen-2020-047230 ◽

2021 ◽

Vol 11 (5) ◽

pp. e047230

Author(s):

Jae-Sung Nam ◽

Yun Ho Roh ◽

Wasan Almazouq Fahad ◽

Hae-Eun Noh ◽

Jong-Gyun Ha ◽

...

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Chronic Rhinosinusitis ◽

Logistic Regression Analysis ◽

Central Obesity ◽

Nasal Polyps ◽

Control Group ◽

Cross Sectional ◽

Cross Sectional Analysis ◽

Sectional Analysis

ObjectivesWe performed a cross-sectional analysis of data from the nationwide Korea National Health and Nutrition Examination Survey to evaluate the association between obesity and chronic rhinosinusitis with nasal polyps (CRSwNP) or without nasal polyp (CRSsNP).DesignRetrospective cross-sectional analysis of health survey data.SettingVoluntary survey of representative South Korean populations.ParticipantsIn total, 32 384 individuals aged 19 years or older with available data on CRS and obesity were included.Primary and secondary outcome measuresDiagnosis of CRSwNP or CRSsNP was performed by trained otolaryngologists through sinus endoscopy and surveys of medical history. General and central obesity was diagnosed using body mass index (BMI) and waist circumference (WC), respectively.MethodsA multivariate logistic regression analysis was used to clarify the association between CRSwNP or CRSsNP and obesity according to BMI and WC. Non-obese individuals were recruited as controls.ResultsThe prevalence of CRSwNP was higher in the general (OR, 1.438; 95% CI, 1.170 to 1.768; p<0.001) and central (OR, 1.251; 95% CI, 1.031 to 1.520; p=0.033) obesity groups than in the control group. Prevalence of CRSsNP was not correlated with obesity. In a logistic regression analysis, olfactory dysfunction (OR, 1.329; 95% CI, 1.137 to 1.553; p<0.001) and purulent discharge (OR, 1.383; 95% CI, 1.193 to 1.603; p<0.001) showed a higher incidence in the central obesity group than in the control group.ConclusionsWe demonstrated an association between CRSwNP and general and central obesity. Further investigations on the mechanism underlying this correlation are necessary for an improved understanding of the pathogenesis of CRSwNP.

Download Full-text

CD133, a Progenitor Cell Marker, is Reduced in Nasal Polyposis and Showed Significant Correlations with TGF-β1 and IL-8

International Archives of Otorhinolaryngology ◽

10.1055/s-0041-1726043 ◽

2021 ◽

Author(s):

Wagner Vargas Souza Lino ◽

André Luis Lacerda Bachi ◽

José Arruda Mendes Neto ◽

Gabriel Caetani ◽

Jônatas Bussador do Amaral ◽

...

Keyword(s):

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Nasal Polyposis ◽

Transforming Growth Factor ◽

Middle Turbinate ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Histologic Analysis ◽

Aspirin Intolerance ◽

Tgf Β1

Abstract Introduction Combination of chronic inflammation and an altered tissue remodeling process are involved in the development of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). Studies demonstrated that mesenchymal stem cells expressing the progenitor gene CD133 were involved in a significant reduction of the chronic inflammatory process in the polypoid tissue. Objective To evaluate the levels of CD133 (Prominin-1) in nasal polypoid tissue and its correlation with interleukin-8 (IL-8) and transforming growth factor β1 (TGF-β1). Methods A total of 74 subjects were divided in the following groups: control group (n = 35); chronic rhinosinusitis with nasal polyps nonpresenting comorbid asthma and aspirin intolerance (CRSwNPnonAI) group (n = 27); and chronic rhinosinusitis with nasal polyps presenting comorbid asthma and aspirin intolerance (CRSwNPAI) group (n = 12). Histologic analysis and also evaluation of the concentration of CD133, IL-8, and TGF-β1 by enzyme-linked immunosorbent assay (ELISA) kits were performed in nasal tissue obtained from nasal polypectomy or from middle turbinate tissue. Results Higher eosinophilic infiltration was found in both CRSwNP groups by histologic analysis. Lower levels of TGF-β1 and IL-8 were observed in both CRSwNP groups when compared with the control group, whereas the CD133 levels were significantly reduced only in the CRSwNPnonAI group compared with the control group. Conclusion It was demonstrated that the nasal mucosa presenting polyposis showed a significant reduction of CD133 levels, and also that this reduction was significantly correlated with the reduction of TGF-β1 levels, but not with IL-8 levels. Therefore, these findings may be involved in the altered inflammatory and remodeling processes observed in the nasal polyposis.

Download Full-text

JAK2 Phosphorylation Signals and Their Associated Cytokines Involved in Chronic Rhinosinusitis with Nasal Polyps and Correlated with Disease Severity

Biomolecules ◽

10.3390/biom11071059 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1059

Author(s):

Yu-Tsai Lin ◽

Wei-Chih Chen ◽

Ming-Hsien Tsai ◽

Jing-Ying Chen ◽

Chih-Yen Chien ◽

...

Keyword(s):

Chronic Rhinosinusitis ◽

Disease Severity ◽

Nasal Polyps ◽

Inflammatory Diseases ◽

Janus Kinase ◽

Sinus Surgery ◽

Control Group ◽

Jak2 Inhibitor ◽

Ifn Γ ◽

Snot 22

Janus kinase 2 (JAK2) is a member of the JAK family that transduces cytokine-mediated signals via the JAKs/STATs (signal transducer and activator of transcription proteins) pathway, which plays an important role in many inflammatory diseases. This study investigates the association of p-JAK2 and JAK2-associated cytokines from nasal polyp (NP) tissue with disease severity, and evaluates the p-JAK2-mediated STATs in chronic rhinosinusitis (CRS) with NP. Sixty-one CRSwNP patients with nasal polyps undergoing endoscopic sinus surgery were enrolled, while the turbinate tissues from 26 nasal obstruction patients were examined as the control group. Elevated levels of p-JAK2 were detected in CRSwNP, and significantly correlated with scores of disease severity (LMK-CT, TPS, and SNOT-22). Expressions of the JAK2-associated cytokines, such as IL-5, IL-6, IL-13, G-CSF, and IFN-γ were significantly higher in CRSwNP than in the controls, while the levels of IL-5, IL-6, IL-13, or G-CSF had positive correlation with scores of disease severity. Moreover, markedly increased expression of p-STAT3 in CRSwNP was observed relative to the control. Taken together, these data showed that the JAK2-associated cytokines including IL-6 and G-CSF may stimulate JAK2 phosphorylation to activate p-STAT3, indicating an association with disease severity and supporting its development of JAK2 inhibitor as a potential therapeutic agent for CRS.

Download Full-text