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1.
Mol Med Rep ; 20(2): 1952-1958, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257460

RESUMO

Electroacupuncture (EA) has been documented as a form of therapy for chronic sinusitis (CRS). The present study aimed to assess the effects of EA combined with interleukin­10 (IL­10) overexpression on CRS in mice, and to investigate the associated mechanisms. A mouse model of CRS was established by the administration of ovalbumin (OVA), and overexpression of IL­10 was induced using virus­encoded IL­10. The experimental groups were as follows: i) Control group; ii) OVA group; iii) OVA + EA group; iv) OVA + empty vector group; v) OVA + vector + EA group; vi) OVA + IL­10 group; and vii) OVA + IL­10 + EA group. Pathological changes and nasal mucus were analyzed using hematoxylin and eosin staining. Interferon­Î³ (IFN­Î³) and IL­10 were detected via reverse­transcription quantitative PCR and western blot analyses. The pseudostratified epithelium of the mucosa of the nasal sinus was impaired following the induction of CRS. Treatment with EA and/or IL­10 reversed the injury. Combination treatment with EA and IL­10 induced synergistic effects. No infiltration of inflammatory cells was observed in the submucosa following EA and IL­10 treatment. Compared with the control group, the expression of IFN­Î³ and IL­10 in the OVA group was reduced. By contrast, EA or the overexpression of IL­10 inhibited this reduction. Furthermore, the combined application of EA and IL­10 had a significantly more potent inhibitory effect on the reduction of IFN­Î³ expression, but not IL­10. Collectively, EA combined with IL­10 induced specific effects on CRS in mice, likely through the upregulation of IFN­Î³ and IL­10. The current study presented mechanistic implications for the application of EA as an alternative treatment for CRS.


Assuntos
Doença Crônica/terapia , Eletroacupuntura/métodos , Pólipos Nasais/terapia , Sinusite/terapia , Animais , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interleucina-10/genética , Camundongos , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Sinusite/genética
2.
Mol Med Rep ; 20(2): 863-870, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173191

RESUMO

CaMKII is a calcium­activated kinase, proved to be modulated by oxidation. Currently, the oxidative activation of CaMKII exists in several models of asthma, chronic rhinosinusitis with nasal polyps, cardiovascular disease, diabetes mellitus, acute ischemic stroke and cancer. Oxidized CaMKII (ox­CaMKII) may be important in several of these diseases. The present review examines the mechanism underlying the oxidative activation of CaMKII and summarizes the current findings associated with the function of ox­CaMKII in inflammatory diseases. Taken together, the findings of this review aim to improve current understanding of the function of ox­CaMKII and provide novel insights for future research.


Assuntos
Asma/enzimologia , Isquemia Encefálica/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Doenças Cardiovasculares/enzimologia , Diabetes Mellitus/enzimologia , Pólipos Nasais/enzimologia , Neoplasias/enzimologia , Sinusite/enzimologia , Animais , Asma/tratamento farmacológico , Asma/genética , Asma/patologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Ativação Enzimática , Expressão Gênica , Humanos , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/genética , Pólipos Nasais/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Oxirredução , Estresse Oxidativo , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sinusite/tratamento farmacológico , Sinusite/genética , Sinusite/patologia
4.
Int Arch Allergy Immunol ; 180(1): 72-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31137020

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a multifaceted disease with a significant genetic component. The importance of taste receptor signaling has recently been highlighted in CRS; single nucleotide polymorphisms (SNPs) of bitter tastant-responsive G-protein-coupled receptors have been linked with CRS and with altered innate immune responses to multiple bacterially derived signals. OBJECTIVE: To determine in CRS the frequency of six SNPs in genes with known bitter tastant signaling function. METHODS: Genomic DNA was isolated from 74 CRS volunteers in West Virginia, and allele frequency was determined and compared with demographically matched data from the 1,000 Genomes database. RESULTS: For two SNPs in a gene recently associated with bitterant signaling regulation, RGS21, there were no associations with CRS (although the frequency of the minor allele of RGS21, rs7528947, was seen to increase with increasing Lund-Mackay CT staging score). Two TAS2R bitter taste receptor gene variants (TAS2R19 rs10772420 and TAS2R38 rs713598), identified in prior CRS genetics studies, were found to have similar associations in this study. CONCLUSION: Unique to our study is the establishment of an association between CRS in this patient population and GNB3 SNP rs5443, a variation in an established G protein component downstream of bitterant receptor signal transduction.


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/genética , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Rinite/diagnóstico , Rinite/genética , Sinusite/diagnóstico , Sinusite/genética , Adulto , Idoso , Alelos , Doença Crônica , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Rinite/imunologia , Fatores de Risco , Sinusite/imunologia
5.
Mol Cells ; 42(4): 345-355, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31082802

RESUMO

Eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most challenging problems in clinical rhinology. FZD5 is a receptor for Wnt5A, and its complex with Wnt5A contributes to activating inflammation and tissue modification. Nasal polyps and eosinophil/non-eosinophil counts are reported to be directly correlated. This study investigated the expression and distribution of FZD5, and the role of eosinophil infiltration and FZD5 in eosinophilic CRSwNP pathogenesis. The prognostic role of eosinophil levels was evaluated in seven patients with CRSwNP. Fifteen patients with CRS were classified based on the percentage of eosinophils in nasal polyp tissue. Methylated genes were detected using methyl-CpG-binding domain sequencing, and qRT-PCR and immunohistochemistry were used to detect FZD5 expression in nasal polyp tissue samples. The results showed that mRNA expression of FZD5 was upregulated in nasal polyps. FZD5 expression was significantly higher in nasal polyp samples from patients with eosinophilic CRSwNP than in those from patients with non-eosinophilic CRSwNP, as indicated by immunohistochemistry. Furthermore, inflammatory cytokine levels were higher in eosinophilic CRSwNP-derived epithelial cells than in normal tissues. In conclusion, FZD5 expression in nasal mucosal epithelial cells is correlated with inflammatory cells and might play a role in the pathogenesis of eosinophilic CRSwNP.


Assuntos
Metilação de DNA , Eosinófilos/metabolismo , Receptores Frizzled/genética , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Adulto , Idoso , Citocinas/metabolismo , Epigênese Genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Receptores Frizzled/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Pólipos Nasais/imunologia , Prognóstico , Regiões Promotoras Genéticas , Rinite/imunologia , Sinusite/imunologia , Regulação para Cima
6.
Acta Otolaryngol ; 139(7): 652-658, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050570

RESUMO

Background: Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and the paranasal sinuses, often associated with an infection by Staphylococcus aureus (S. aureus). Disturbance in the function of ion channels is regarded as an etiological factor for pathogenesis of CRS. Aims: The study aims to measure the mRNA expression of the ENaC and CFTR ion channels in nasal epithelial cells (NECs) and to investigate the effect of both the budesonide and S. aureus on these ion channels. Materials and method: NECs biopsies obtained from healthy volunteers and patients with CRS. NECs were infected with S. aureus strains and/or budesonide to study the mRNA expression levels of the ENaC and CFTR ion channels. Results: The mRNA expression level of CFTR was increased while that of ENaC was decreased. S. aureus infection and budesonide treatment induced a significant modulation of ENaC and CFTR ion channels expression. Conclusion: The CFTR and ENaC ion channel physiology are of importance in the pathogenesis of CRS. Exposure to S. aureus infection and treatment with budesonide modulated the mRNA expression of CFTR and ENaC ion channels. Significance: Better understanding of the pathophysiology of CRS.


Assuntos
Budesonida/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulação da Expressão Gênica , Rinite/genética , Sinusite/genética , Infecções Estafilocócicas/genética , Adulto , Análise de Variância , Estudos de Casos e Controles , Doença Crônica , Canais Epiteliais de Sódio/efeitos dos fármacos , Canais Epiteliais de Sódio/metabolismo , Feminino , Seguimentos , Humanos , Transporte de Íons , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Valores de Referência , Rinite/tratamento farmacológico , Rinite/microbiologia , Medição de Risco , Transdução de Sinais/genética , Sinusite/tratamento farmacológico , Sinusite/microbiologia , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Regulação para Cima
7.
Int Arch Allergy Immunol ; 179(4): 304-319, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30982052

RESUMO

OBJECTIVES: To characterize the epithelial-mesenchymal transition (EMT) in chronic rhinosinusitis with nasal polyps (CRSwNP) and to investigate the mechanism by which microRNA-21 (miR-21) regulates EMT in CRSwNP. METHOD: (1) Tissue experiments: Mucosa tissues were collected from 13 patients with CRSwNP and 12 patients with CRS without nasal polyps (CRSsNP), as well as 11 patients without CRS (controls). Protein localization and quantification were achieved by immunofluorescence staining and Western blotting, involving the epithelial marker protein E-cadherin and the mesenchymal marker proteins α-smooth muscle actin (α-SMA), fibronectin, and vimentin. Quantitative RT-PCR was used to detect the relative expression levels of miR-21 and TGF-ß1 mRNAs. (2) Cellular experiments: Primary human nasal epithelial cells (PHNECs) treated with TGF-ß1, or TGF-ß1 with miR-21 inhibitor, or miR-21 mimics alone were observed for morphology changes under a phase-contrast microscope. The expression levels of epithelial/mesenchymal marker proteins were determined as aforementioned. PTEN and phosphorylated Akt were detected by Western blotting. RESULTS: (1) Tissue experiments: Compared with the CRSsNP and control groups, the expression of E-cadherin was downregulated in the CRSwNP group, whereas the expression of TGF-ß1, α-SMA, fibronectin, and vimentin was upregulated. The expression levels of miR-21 and TGF-ß1 mRNAs in CRSwNP were significantly higher than those in CRSsNP and controls. (2) Cellular experiments: TGF-ß1 induced EMT-like transformation in PHNECs, featured by changes in cell morphology and upregulation of mesenchymal proteins and miR-21. The miR-21 inhibitor, as well as the Akt-specific -inhibitor, suppressed TGF-ß1-induced EMT. Mechanically, downregulation of miR-21 resulted in increased PTEN and decreased Akt phosphorylation. Furthermore, overexpression of miR-21 had the opposite effects. CONCLUSIONS: Our findings suggest that the TGF-ß1-miR-21-PTEN-Akt axis may contribute to the pathogenesis of CRSwNP. miR-21 might be a reliable target for treating nasal polyp genesis through EMT suppression. Moreover, miR-21 inhibitors could be a novel class of antipolyp drug that modulates PTEN expression and Akt activation. In addition, further investigation regarding the reason underlying miR-21 overexpression in CRSwNP could provide a molecular target for novel treatment strategies for nasal polyposis.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/genética , Mucosa Nasal/fisiologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Fator de Crescimento Transformador beta1/genética , Adolescente , Adulto , Idoso , Células Cultivadas , Criança , Doença Crônica , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rinite/genética , Sinusite/genética , Fator de Crescimento Transformador beta1/metabolismo , Adulto Jovem
9.
Mol Med Rep ; 19(5): 3855-3863, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864741

RESUMO

Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most prevalent chronic diseases. In patients with CRSwNP, the present study performed comprehensive bioinformatics analyses to characterize the transcriptome profiles of mRNAs and long non­coding RNAs (lncRNAs). A total of 265 differentially expressed lncRNAs and 994 mRNAs were identified. The majority of up­ and downregulated differentially expressed genes were significantly enriched in the biological process of 'signal transduction'. The most significantly enriched molecular function was 'protein binding' and the most significantly enriched cellular component was 'membrane'. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis led to identification of several significantly enriched pathways [false discovery rate (FDR)<0.05], including 'cytokine­cytokine receptor interaction' (FDR=3.94x1016) and 'cell adhesion molecules' (CAMs) (FDR=1.28x10­5). Key differentially expressed lncRNAs were identified, including lncRNA XLOC_010280, which regulates chemokine (C­C motif) ligand 18 (CCL18) and inflammation, and RP11­798M19.6, which regulates polypeptide N­acetylgalactosaminyltransferase 7 (GALNT7) and cell proliferation. Based on the results of reverse transcription­quantitative polymerase chain reaction, except for CCL8, neural precursor cell expressed developmentally downregulated gene 4­like and GALNT7, the expression of 3 other selected genes was consistent with the results of integrated analysis. The results of the present study provide a foundation for future investigations into mRNAs and lncRNAs as diagnostic and therapeutic targets in CRSwNP.


Assuntos
Perfilação da Expressão Gênica , Genoma Humano , Pólipos Nasais/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Estudos de Casos e Controles , Doença Crônica , Biologia Computacional , Redes Reguladoras de Genes , Humanos , Pólipos Nasais/patologia , Mapas de Interação de Proteínas , RNA Mensageiro/genética , Rinite/genética , Rinite/patologia , Transdução de Sinais , Sinusite/genética , Sinusite/patologia
10.
Int Immunopharmacol ; 71: 169-180, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909132

RESUMO

BACKGROUND: Autophagy is a lysosomal degradation pathway that protects the body and is essential for cell survival and differentiation. Mucins (MUCs) are important components of secreted mucus, mucin (MUC)5 AC is the major MUC secreted in the normal airway. OBJECTIVE: Investigated the role of autophagy in pathogenic mucin (MUC)5 AC production during chronic rhinosinusitis (CRS). METHODS: The expression of human neutrophil elastase (HNE) and the autophagic proteins microtubule-associated protein 1 light chain (LC)3B-II, c-Jun N-terminal kinase (JNK), c-Jun, and MUC5AC were analyzed in the sinonasal mucosa and human nasal epithelial cells (HNECs) using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR). Autophagic vacuoles were studied using transmission electron microscopy (TEM). Primary HNECs were treated with HNE, bafilomycin A1, and SP600125. In some experiments, cultured primary HNECs were transfected with small interfering RNAs (siRNAs) to target Beclin-1 (BECN1; BECN1-siRNA), autophagy-related gene 5 (Atg5; Atg5-siRNA), and c-Jun (c-Jun-siRNA). Cultured cells were analyzed using western blotting, qRT-PCR, and ELISA. RESULTS: In CRS patients, both with and without nasal polyps, the expression levels of HNE, LC3B, JNK, c-Jun, and MUC5AC were upregulated. Bafilomycin A1 upregulated LC3B-II expression and inhibited MUC secretion in HNE-treated normal primary HNECs. Autophagosomes were observed in HNE-treated primary HNECs using TEM. HNE-induced secretion of MUC5AC was suppressed in normal primary HNECs by BECN1-siRNA, Atg5-siRNA, c-Jun-siRNA, and SP600125. CONCLUSIONS: In HNE-induced CRS, autophagy increases the secretion of MUC5AC by promoting the phosphorylation of JNK and c-Jun.


Assuntos
Autofagia , Mucina-5AC/metabolismo , Mucosa Nasal/fisiologia , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Adolescente , Adulto , Idoso , Células Cultivadas , Criança , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucina-5AC/genética , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Regulação para Cima , Adulto Jovem
13.
Nat Genet ; 51(2): 267-276, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643255

RESUMO

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.


Assuntos
Araquidonato 15-Lipoxigenase/genética , Variação Genética/genética , Pólipos Nasais/genética , Sinusite/genética , Adulto , Asma/genética , Doença Crônica , Eosinófilos/patologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Islândia , Contagem de Leucócitos/métodos , Masculino , Pólipos Nasais/patologia , Sinusite/patologia
14.
Am J Otolaryngol ; 40(2): 191-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30661889

RESUMO

PURPOSE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory disease of yet unknown etiology. The purpose of this study was to uncover key genes and pathways related to the pathogenesis of CRSwNP via bioinformatics approaches. MATERIALS AND METHODS: The gene expression profile of GSE36830 extracted from Gene Expression Omnibus database was used to screen differentially expressed genes (DEGs) between nasal polyp samples and control samples. Furthermore, functional and pathway enrichment analysis was performed using the clusterProfiler package in R language. In addition, protein-protein interaction (PPI) network was constructed by STRING database and functional modules were detected using Molecular Complex Detection algorithm. RESULTS: A total of 538 DEGs (326 up-regulated and 212 down-regulated) were identified. The most significantly enriched pathways for up-regulated and down-regulated genes were hematopoietic cell lineage and salivary secretion, respectively. Moreover, twenty hub genes with high connectivity degrees were selected from the PPI network, such as TYRO protein tyrosine kinase binding protein (TYROBP), G protein subunit gamma 2 (GNG2), CCR7, and CCR3. Besides, six important modules were obtained, which were highly associated with chemokine signaling pathway, Th1 and Th2 cell differentiation, complement and coagulation cascades, cell cycle, systemic lupus erythematosus, and Staphylococcus aureus infection. CONCLUSIONS: The results of this study may provide new insights into potential molecular mechanisms of CRSwNP. Nevertheless, further experiments are needed to confirm these findings.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Quimiocinas , Biologia Computacional/métodos , Proteínas de Ligação ao GTP/genética , Perfilação da Expressão Gênica/métodos , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Pólipos Nasais/complicações , Pólipos Nasais/genética , Receptores CCR3/genética , Receptores CCR7/genética , Rinite/complicações , Rinite/genética , Transdução de Sinais/genética , Sinusite/complicações , Sinusite/genética , Transcriptoma , Regulação para Baixo/genética , Humanos , Regulação para Cima/genética
15.
Int Forum Allergy Rhinol ; 9(1): 114-119, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30281933

RESUMO

BACKGROUND: Oxidative stress exacerbates lower airway diseases including asthma and chronic obstructive pulmonary disease (COPD); however, its role in upper airway (sinonasal) chronic inflammatory disorders is less clear. Nuclear erythroid 2 p45-related factor (Nrf2) is an endogenous mechanism that upon activation invokes an antioxidant response pathway via nuclear translocation and upregulation of cytoprotective genes. We sought to determine whether deletion of Nrf2 enhances susceptibility to allergic sinonasal inflammation in vivo. METHODS: Nrf2-/- mice were subjected to the ovalbumin (Ova)-induced murine model of rhinosinusitis and indices of sinonasal inflammation and epithelial barrier dysfunction were assessed. RESULTS: We show that deletion of Nrf2 results in enhances indices of allergen-induced sinonasal inflammation including aggravated eosinophil accumulation and goblet cell hyperplasia. An exaggerated increase in epithelial derived inflammatory cytokines including interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP) was observed in the nasal lavage fluid and sinonasal mucosal tissue of Nrf2-/- mice. Furthermore, Nrf2-/- mice showed heightened Ova-induced barrier dysfunction as measured by serum albumin accumulation in nasal lavage fluid of mice. CONCLUSION: These data show that the endogenous Nrf2 pathway limits Ova-induced sinonasal inflammation, epithelial derived inflammatory cytokine production, and epithelial barrier dysfunction in vivo and identify a potential therapeutic target in the management of allergic sinonasal inflammatory disorders. This is the first study to our knowledge which shows that Nrf2 regulates allergic inflammation in the sinonasal cavity in vivo.


Assuntos
Eosinófilos/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Seios Paranasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Animais , Movimento Celular , Doença Crônica , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Rinite/genética , Sinusite/genética
16.
Auris Nasus Larynx ; 46(3): 374-383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30243753

RESUMO

OBJECTIVE: Recently, JESREC score and mucosal eosinophil count have been used to diagnose eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, it remains unknown whether the subtypes of CRS diagnosed by these criteria have different endotypes. In the present study, we investigated whether JESREC score and mucosal eosinophil count were appropriate for classification of CRS subgroups into endotypes. METHODS: A cross-sectional study involving 71 consecutive patients with CRS with nasal polyps (CRSwNP) and 13 control patients was performed. Nasal polyp tissues from CRSwNP patients and uncinate process tissues from control patients were collected for analysis of inflammatory cells by immunohistochemistry and measurement of cytokines and chemokines by ELISA and quantitative real-time PCR. We compared the differences between subtypes according to JESREC score and mucosal eosinophil count and investigated the subgroups with different endotypes by cluster analysis and principal component analysis. RESULTS: In the 71 CRSwNP patients, 9 patients had JESREC score <11 and mucosal eosinophil count <70/HPF (Group A), 20 patients had JESREC score ≥11 and mucosal eosinophil count <70/HPF (Group C), and 42 patients had JESREC score ≥11 and mucosal eosinophil count ≥70/high-power field (HPF) (Group D). Semiquantitative analysis of inflammatory cells showed that eosinophils, neutrophils, macrophages, mast cells, and basophils differed significantly between the subgroups. At the mRNA level, CLC, IL5, IL13, CCL11, CCL24, CCL26, POSTN, CSF3, and IL8 showed significant differences. At the protein level, eotaxin-2/CCL24, eotaxin-3/CCL26, and G-CSF had significant differences. Cluster analysis using gene expression levels in 55 CRS patients and 11 control patients revealed that the patients could be classified into five clusters. Cluster 1 (n=27) contained all patients with Group D. Cluster 2 (n=11) comprised all control patients. Cluster 3 (n=4) included mixed subtypes: one with Group A and three with Group D. Cluster 4 (n=7) and Cluster 5 (n=17) contained all patients with Groups A and C, respectively. Furthermore, the principal component analysis revealed that the subtypes had different characteristics. CONCLUSION: CRS subtypes based on JESREC score and mucosal eosinophil count showed different inflammatory patterns, and unsupervised statistical analyses supported the classification that can predict endotypes. From these results, we concluded that the classification based on JESREC score and mucosal eosinophil count was useful for predicting CRS endotypes.


Assuntos
Citocinas/imunologia , Eosinofilia/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Doença Crônica , Citocinas/genética , Eosinofilia/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Pólipos Nasais/genética , Análise de Componente Principal , RNA Mensageiro/metabolismo , Rinite/genética , Sinusite/genética
17.
Int Forum Allergy Rhinol ; 9(1): 106-113, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30378273

RESUMO

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a persistent sinonasal mucosa inflammatory disease. MicroRNAs (miRNAs) that are involved in the pathogenesis of CRSwNP in Northern China remain unknown. METHODS: A miRCURY™ LNA Array was used to analyze miRNA profiles in nasal mucosa tissues of CRSwNP patients (n = 19) and healthy controls (n = 10). Subsequent pathways were predicted by DIANA-mirPath software. RESULTS: Five upregulated miRNAs, including miR-210-5p, miR-3178, miR-585-3p, miR-3146, and miR-320e, and 19 downregulated miRNAs, including miR-32-3p, miR-1299, miR-3196, miR-3924, and miR-548e-3p, were differentially expressed (p < 0.05, fold change >2) in tissues of CRSwNP vs controls. Utilizing the Kyoto Encyclopedia of Genes and Genomes database (KEGG), which is an online database for pathway mapping, mucin type O-glycan biosynthesis pathway was significantly enriched in upregulated miRNAs. Transforming growth factor-beta (TGF-ß), transient receptor potential (TRP) channels, and the mitogen-activated protein kinase (MAPK) signaling pathway were significantly linked to downregulated miRNAs. CONCLUSION: The mucin type O-glycan biosynthesis pathway and TGF-ß signaling pathway are regulated by miRNAs, which could be our focus in the future studies.


Assuntos
MicroRNAs/genética , Mucosa Nasal/fisiologia , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Adulto , China , Doença Crônica , Feminino , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Mucinas/biossíntese , Pólipos Nasais/metabolismo , Mapas de Interação de Proteínas , Rinite/metabolismo , Transdução de Sinais , Sinusite/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
18.
Int Forum Allergy Rhinol ; 9(3): 292-297, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30472785

RESUMO

BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves pulmonary function in cystic fibrosis (CF) patients with at least 1 copy of the G551D CFTR mutation. The purpose of this study is to evaluate the impact of ivacaftor on chronic rhinosinusitis (CRS) symptoms in this population. METHODS: The G551D Observational (GOAL) study was a multicenter prospective cohort study enrolling CF patients ≥6 years with at least 1 G551D mutation. Subjects were provided 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaires prior to ivacaftor therapy and at 1, 3, and 6 months afterward. The impact on rhinologic (R), psychological (P), sleep (S), and ear/facial (E) quality of life (QOL) domains was evaluated separately. RESULTS: Of 153 subjects, 129 (84%) completed all questionnaires. Typical baseline symptom burden was low (75% with scores <1) and degree of improvement (ie, reduced scores) was greater with higher baseline scores. SNOT-20 decreased, reflecting improvement, at all follow-up intervals (1 month: [mean change ± standard deviation] -0.25 ± 0.53, p < 0.01; 3 months; -0.29 ± 0.58, p < 0.01; 6 months: -0.21 ± 0.58, p = 0.02), but less than the prespecified minimal clinically important difference (0.8). Significant improvement was observed at 1, 3, and 6 months in the R domain (1 month: -0.24, p < 0.01; 3 months: -0.34, p < 0.01; 6 months: -0.25, p < 0.01) and P domain (1 month: -0.25, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.26, p < 0.01), and 1 and 3 months in the S domain (1 months: -0.35, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.18, p = 0.07). There was no improvement in the E domain at any time point. CONCLUSION: Ivacaftor improves QOL in the R, P, and S domains in G551D CF patients, although QOL instruments validated for CRS may not translate well to CF CRS patients because symptom burden was surprisingly low.


Assuntos
Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminofenóis/farmacologia , Criança , Doença Crônica , Estudos de Coortes , Fibrose Cística/genética , Fibrose Cística/psicologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Mutação/genética , Estudos Prospectivos , Qualidade de Vida , Quinolonas/farmacologia , Rinite/genética , Rinite/psicologia , Sinusite/genética , Sinusite/psicologia , Sono , Inquéritos e Questionários , Adulto Jovem
19.
Vestn Otorinolaringol ; 84(6): 42-47, 2019.
Artigo em Russo | MEDLINE | ID: mdl-32027322

RESUMO

INTRODUCTION: Rhinosinusitis with nasal polyps (CRSwNP) is often followed by a range of comorbid states, influence of which on the course of the main pathology process remains insufficiently studied. PURPOSE: To study the gene expression level of cytokines potentially talking part in the development of inflammation in nasal polyps with different phenotypes of CRSwNP. MATERIAL AND METHODS: All the patients with CRSwNP were divided into 4 equal groups, 36 patients in each subgroup: group 1 - CRSwNP without comorbid pathology; group 2 - CRSwNP+atopy; group 3 - CRSwNP + non-allergic bronchial asthma (BA); control group 4 - 36 patients diagnosed with hypertrophic rhinitis without atopy and without bronchial asthma. Using the real-time polymerase chain reaction (Real-Time PCR) method, the study of expression level of mRNA genes coding proteins IL-1ß, IL-4, IL-5, IL-13, IL-17F, IL-25, IFN-y, TSLP in polyp tissue was conducted. RESULTS: The statistically proved difference of expression level of cytokines depending on the CRSwNP phenotype was educed. If CRSwNP and atopy were combined, the gene expression level of all studied cytokines was statistically higher than that of CRSwNP without comorbid pathology; and the expression level of IL-17F, IL-25 and TSLP was more intense that in the group of CRSwNP + BA. There was no difference between the patients with comorbid allergy and comorbid BA regarding the gene expression of IFN-y, IL-5 and IL-13 cytokines. Among different phenotypes of CRSwNP no difference in IL-1ß expression level was detected, which evidences of persisting inflammatory process, and the IL-4 gene expression level was lower than the detection level in all the groups. CONCLUSION: With different CRSwNP phenotypes different inflammatory patterns are detected, which indicates different character of the pathology process course among these groups of patients. Higher expression level of cytokine genes, which are a marker of epithelial damage of IL-25 and TSLP, is found only among the patients with CRSwNP and atopy. It suggests that forming of CRSwNP without comorbid pathology is connected with other pathologic mechanisms, not with the damage to epithelial barrier. If CRSwNP + BA and CRSwNP + atopy were combined, the expression level of IFN-y, IL-5, IL-13 and IL-17F genes was higher than the one in the group of patients with CRSwNP without comorbid pathology. In view of obtained data, all the patients with CRSwNP shall be screened for bronchial asthma and the allergy diagnostic shall be conducted.


Assuntos
Citocinas , Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Citocinas/genética , Citocinas/metabolismo , Humanos , Pólipos Nasais/genética , Fenótipo , Rinite/genética , Sinusite/genética , Transcriptoma
20.
Vestn Otorinolaringol ; 83(5): 49-54, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30412176

RESUMO

The objective of the present study was to elucidate the possible correlations between the vitamin D3 level in the blood serum and lactase gene polymorphism (LCT-13910 T>C) in the patients presenting with chronic polypous rhinosinusitis (CPRS). The study included 50 patients with this condition and 14 subjects comprising the control group. The variants of lactase gene polymorphism (LCT-13910 T>C) were identified with the use of polymerase chain reaction (PCR) in real time. The total level of serum vitamin D3 (VD3) was determined by means of the immunochemical analysis (the electrochemiluminescence technique). In the group of patients presenting with chronic polypous rhinosinusitis, the level of VD3 in the blood serum ranged from 48 nm/l to 85 nm/l (mean 60 nm/l) compared with that in the patients of the control group (from 78 nm/l to 112 nm/l; mean 97 nm/l) . The level of vitamin D3 'below the normal values' was documented in 71% of the patients with CPRS in comparison with 7% in the control subjects. Lactase gene polymorphism (LCT-13910 CC, CT) suggesting pronounced and latent hypolactasia was identified in 94% of the patients with CPRS compared with 78.6% in the control group. The occurrence of the CC genotype in the patients of both study groups was virtually identical: 52% in the patients presenting with chronic polypous rhinosinusitis and 57% in the control group. CT polymorphism was identified in 42% of the patients with CPRS and in 21% of the control subjects. The significant difference between the patients of the two groups was documented for the occurrence of TT polymorphism: 6% among the patients with CPRS and 21% in the controls (i.e. much higher in the healthy subjects). There was no significant difference between the serum levels of vitamin D3 either among the patients with CPRS having LCT-13910 gene polymorphisms (CC, CT, TT) or among the control subjects. It is concluded that the study revealed the higher levels of vitamin D3 in the blood sera from the control subjects in comparison with that in the patients with chronic polypous rhinosinusitis. Moreover, the patients of the latter group more frequently exhibited the variant of the LCT CT-13910 gene polymorphism suggesting latent hypolactasia whereas the subjects comprising the control group more frequently had the variant of the LCT CT-13910 gene polymorphism indicative of the normal tolerance of lactose.


Assuntos
Colecalciferol , Lactase , Intolerância à Lactose , Pólipos Nasais , Rinite , Sinusite , Colecalciferol/farmacologia , Genótipo , Humanos , Lactase/biossíntese , Lactase/efeitos dos fármacos , Lactase/genética , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/genética , Polimorfismo de Nucleotídeo Único , Rinite/tratamento farmacológico , Rinite/genética , Soro , Sinusite/tratamento farmacológico , Sinusite/genética
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