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1.
Life Sci ; 284: 119922, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480930

RESUMO

AIMS: Notch signaling is closely related to a variety of diseases, but the role of Notch2 in allergic rhinitis (AR) remain unclear. This study was performed to investigate the effects of Notch2 on the differentiation of Treg cells and on the inflammatory response of AR. MATERIALS AND METHODS: Peripheral blood (including 101 AR patients and 66 Controls) and nasal mucosa (including 19 AR patients and 17 Controls) were collected to detect the expression levels of Notch2, NICD2 and FOXP3. CD4+ T cells of human origin were selected to detect the effects of Notch2 on the differentiation of Treg cells and FOXP3. An AR mouse model was established, and lentiviruses overexpressing Notch2 were administered. Then, allergic symptoms, OVA-sIgE titers, nasal mucosal inflammation, Th1/Th2/Th17 cytokines and splenic Treg cells were assessed. KEY FINDINGS: Compared with that in the Control group, the expression of Notch2 in the AR group was decreased, and Notch2 expression was negatively correlated with the degree of allergy (P < 0.01). The expression levels of Notch2, NICD2 and FOXP3 were decreased in the nasal mucosa of AR patients. Notch2 can promote the differentiation of human Treg cells in vitro (P < 0.05), and Notch2 can directly promote FOXP3 transcription. Animal experiments showed after the upregulation of Notch2 expression, the allergic inflammatory of mice with AR was reduced, the differentiation of Treg cells was increased, and the imbalance of T cells was reversed (P < 0.05). SIGNIFICANCE: Notch2 promotes the differentiation of Treg cells by upregulating FOXP3 expression, thus significantly inhibiting the inflammatory response of AR.


Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/metabolismo , Receptor Notch2/metabolismo , Rinite Alérgica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Inflamação/patologia , Lentivirus/metabolismo , Camundongos Endogâmicos C57BL , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Receptor Notch2/sangue , Rinite Alérgica/sangue , Índice de Gravidade de Doença , Transcrição Genética
2.
Tohoku J Exp Med ; 255(1): 19-25, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497164

RESUMO

Airborne fine particulate matter with an aerodynamic diameter equal to or smaller than 2.5 µm (abbreviated as PM2.5) increases the risk of nasal lesions, but the underlying molecular mechanism has not been fully elucidated. In the atmosphere, the composition of PM2.5 collected varies in physical and chemical properties, which affects its damage to human health. Thus, we constructed artificial PM2.5 particles based on actual PM2.5 and investigated the in vivo effects of artificial PM2.5 exposure on the oxidative stress, inflammatory response, and nasal mucosa morphology of rats. The results showed that artificial PM2.5 is comparable in composition ratio, size, and morphology to actual PM2.5. This in vivo study indicated that artificial PM2.5 exposure reduces total superoxide dismutase and glutathione peroxidase activities, elevates malondialdehyde content in the nasal mucosa, and induces increased levels of pro-inflammatory mediators, including interleukin-1, interleukin-6 and tumor necrosis factor-α. Our data shows that artificial PM2.5 particles could be used for experimental study of PM2.5 toxicology, ensuring that the physical and chemical properties of experimental PM2.5 are relatively constant and allowing for repeatability of this research. Oxidative damage and inflammatory response may be the toxic mechanisms that cause nasal lesions after exposure to artificial PM2.5.


Assuntos
Inflamação/etiologia , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Poluentes Atmosféricos/química , Poluentes Atmosféricos/toxicidade , Animais , Feminino , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Exposição por Inalação , Malondialdeído/metabolismo , Modelos Animais , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Tamanho da Partícula , Material Particulado/química , Ratos , Ratos Sprague-Dawley
3.
Artigo em Chinês | MEDLINE | ID: mdl-34304543

RESUMO

Interleukin-8(IL-8) is an inflammatory factor secreted by multiple cells. It has a variety of biological effects such as trending inflammatory cells and promoting angiogenesis in the body. Currently, it is found to play an important role in promoting airway inflammation. Chronic rhinosinusitis is a chronic inflammatory disease of the nasal cavity and sinus mucosa. Under the stimulation of a variety of factors, the secretion of IL-8 in the nasal mucosa and nasal polyps of CRS patients could increase. Therefore, it can cause inflammation and mucosal damage by trending chemotaxis neutrophils and eosinophils.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Interleucina-8 , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia
4.
Signal Transduct Target Ther ; 6(1): 292, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330889

RESUMO

Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN, and NRP1, have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.


Assuntos
COVID-19/imunologia , Comunicação Celular/imunologia , Leucócitos Mononucleares/imunologia , Mucosa Nasal/imunologia , SARS-CoV-2/imunologia , Caracteres Sexuais , Adulto , Idoso , COVID-19/patologia , Feminino , Humanos , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Análise de Célula Única
5.
Front Immunol ; 12: 530488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936025

RESUMO

Background: CRSwNP is an inflammatory disease but the mechanism is not yet fully understood. MiR-21, a member of miRNAs, has been reported to play roles in mediating inflammation. However, the expression of miR-21 and its role in patients with CRSwNP remain elusive. Methods: Turbinates from control subjects, uncinate processes from CRSsNP, polyp tissues from CRSwNP, and nasal epithelial cells brushed from nasal mucosa were collected. The expression of miR-21 and cytokines in nasal tissues and epithelial cells were detected by qPCR. The localization of miR-21 was detected by ISH, and its target was identified by bioinformation analysis, qPCR, IHC, WB, and luciferase reporter system. The protein and mRNA of PDCD4 and NF-κB P65 were determined by WB and qPCR after miR-21 transfection in HNEpC. The role of miR-21 on cytokines was analyzed in HNEpC and nasal polyp explants. Results: MiR-21 was upregulated in CRSwNP relative to control subjects by qPCR, which was determined mainly in nasal epithelial cells of CRSwNP by ISH. Both pro-inflammation cytokines (IL-1ß, IL-6, IL-8, IL-25, and TSLP) and a suppressive cytokine (IL-10) were overexpressed in the epithelial cells of CRSwNP. The expression of miR-21 was positively correlated with IL-10 and negatively correlated with IL-6, IL-8, IL-33, and TSLP in the epithelial cells of CRSwNP. As a potential target of miR-21, the expression of PDCD4 was negatively correlated with miR-21 in CRSwNP. In HNEpC, miR-21 could reduce the expression of PDCD4 at both mRNA and protein levels, and bioinformation analysis and luciferase reporter system confirmed PDCD4 as one target of miR-21. Furthermore, miR-21 could decrease the activation of NF-κB and increase IL-10 mRNA. Both SEB and LPS could elevate miR-21, with IL-25, IL-33, TSLP induced by SEB and IL-1ß, IL-6, IL-8 induced by LPS, while the miR-21 could regulate the expression of IL-33, TSLP, IL-1ß, IL- 6 and IL-8 in vitro and ex vivo. Clinically, miR-21 expression was inversely correlated with the Lund-Mackay CT scores and the Lund-Kennedy scores in CRSwNP. Conclusion: MiR-21 could be a prominent negative feedback factor in the inflammation process to attenuate the expression of pro-inflammatory cytokines, thereby playing an anti-inflammation role in CRSwNP.


Assuntos
Inflamação/genética , MicroRNAs/genética , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Adolescente , Adulto , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Doença Crônica , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Adulto Jovem
6.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34003804

RESUMO

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.


Assuntos
COVID-19/virologia , Interações entre Hospedeiro e Microrganismos , Mucosa Nasal/virologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/patologia , COVID-19/fisiopatologia , Diferenciação Celular , Cílios/patologia , Cílios/fisiologia , Cílios/virologia , Furina/genética , Furina/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Macaca , Modelos Biológicos , Mucosa Nasal/patologia , Mucosa Nasal/fisiopatologia , Pandemias , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA-Seq , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Células-Tronco/patologia , Células-Tronco/virologia , Internalização do Vírus , Replicação Viral/genética , Replicação Viral/fisiologia
8.
J Virol ; 95(14): e0013021, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-33893170

RESUMO

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.


Assuntos
COVID-19/imunologia , Imunidade Inata , Pulmão/imunologia , Mucosa Nasal/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/patologia , Chlorocebus aethiops , Cães , Humanos , Influenza Humana/imunologia , Influenza Humana/patologia , Pulmão/patologia , Células Madin Darby de Rim Canino , Mucosa Nasal/patologia , Mucosa Nasal/virologia , Especificidade de Órgãos/imunologia , RNA Mensageiro/imunologia , RNA Viral/imunologia , Células Vero
9.
Laryngoscope ; 131(10): 2269-2276, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33856051

RESUMO

OBJECTIVES/HYPOTHESIS: The ideal strategy in the treatment of mucosal melanoma of the head and neck (MMHN) remains unclear. Our objective was to evaluate the importance of surgical margins, radiotherapy, and systemic therapy in MMHN. STUDY DESIGN: Retrospective Single Institutional Review. METHODS: Retrospective review of patients with MMHN treated at a tertiary care oncology center between 1999 and 2016. RESULTS: Seventy-six patients were included, 60 of whom were treated with curative intent. Negative or close margins compared with positive margins were associated with higher 3-year overall survival (OS) (62% vs. 29% vs. 13% P = .012), disease-free survival (33% vs. 29% vs. 4% P = .003), and distant control (48% vs. 29% vs. 22% P = .039). Cases with pre-/postoperative radiotherapy had a marginally higher locoregional control versus without (69% vs. 59%, P = .117). Immunotherapy for recurrent and/or metastatic disease was associated with an increase in 3-year OS (15% vs. 3% P = .01). CONCLUSION: Achieving negative surgical margins is relevant in disease control. Despite small sample size, our data suggest that radiotherapy may enhance surgical outcomes. Immunotherapy has therapeutic benefit. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2269-2276, 2021.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Melanoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imunoterapia/métodos , Imunoterapia/estatística & dados numéricos , Masculino , Margens de Excisão , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Mucosa Nasal/patologia , Mucosa Nasal/cirurgia , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/estatística & dados numéricos , Recidiva Local de Neoplasia/prevenção & controle , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Taxa de Sobrevida
10.
Int J Mol Sci ; 22(9)2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923202

RESUMO

The emergence of highly effective CFTR modulator therapy has led to significant improvements in health care for most patients with cystic fibrosis (CF). For some, however, these therapies remain inaccessible due to the rarity of their individual CFTR variants, or due to a lack of biologic activity of the available therapies for certain variants. One proposed method of addressing this gap is the use of primary human cell-based models, which allow preclinical therapeutic testing and physiologic assessment of relevant tissue at the individual level. Nasal cells represent one such tissue source and have emerged as a powerful model for individual disease study. The ex vivo culture of nasal cells has evolved over time, and modern nasal cell models are beginning to be utilized to predict patient outcomes. This review will discuss both historical and current state-of-the art use of nasal cells for study in CF, with a particular focus on the use of such models to inform personalized patient care.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/patologia , Células Epiteliais/patologia , Modelos Biológicos , Mucosa Nasal/patologia , Medicina de Precisão , Animais , Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Humanos , Mucosa Nasal/metabolismo
11.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803422

RESUMO

Psychological stress exacerbates mast cell (MC)-dependent inflammation, including nasal allergy, but the underlying mechanisms are not thoroughly understood. Because the key stress-mediating neurohormone, corticotropin-releasing hormone (CRH), induces human skin MC degranulation, we hypothesized that CRH may be a key player in stress-aggravated nasal allergy. In the current study, we probed this hypothesis in human nasal mucosa MCs (hM-MCs) in situ using nasal polyp organ culture and tested whether CRH is required for murine M-MC activation by perceived stress in vivo. CRH stimulation significantly increased the number of hM-MCs, stimulated both their degranulation and proliferation ex vivo, and increased stem cell factor (SCF) expression in human nasal mucosa epithelium. CRH also sensitized hM-MCs to further CRH stimulation and promoted a pro-inflammatory hM-MC phenotype. The CRH-induced increase in hM-MCs was mitigated by co-administration of CRH receptor type 1 (CRH-R1)-specific antagonist antalarmin, CRH-R1 small interfering RNA (siRNA), or SCF-neutralizing antibody. In vivo, restraint stress significantly increased the number and degranulation of murine M-MCs compared with sham-stressed mice. This effect was mitigated by intranasal antalarmin. Our data suggest that CRH is a major activator of hM-MC in nasal mucosa, in part via promoting SCF production, and that CRH-R1 antagonists such as antalarmin are promising candidate therapeutics for nasal mucosa neuroinflammation induced by perceived stress.


Assuntos
Degranulação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Mastócitos/metabolismo , Mucosa Nasal/metabolismo , Rinite Alérgica/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Rinite Alérgica/patologia
12.
Biochem Biophys Res Commun ; 554: 1-6, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33770685

RESUMO

Exposure to fine particulate matter (PM2.5) increases the incidence of allergic rhinitis (AR). microRNA (miRNA) can regulate cell proliferation, invasion and apoptosis. However, the mechanism of miR-338-3p in mediating PM2.5-induced autophagy in AR animal models remains unknown. To explore the mechanism of miR-338-3p in PM2.5-induced autophagy in AR, the human nasal epithelium cells and AR model exposed to PM2.5 were deployed. The results showed that miR-338-3p was down-regulated in both nasal mucosa of PM2.5-exacerbated AR rat models and PM2.5-treated RPMI-2650 cells. Forced expression of miR-338-3p could inhibit autophagy in vitro. miR-338-3p specifically bound to UBE2Q1 3'-untranslated region (3' UTR) and negatively regulated its expression. Overexpression of UBE2Q1 attenuated the inhibitory effects of miR-338-3p on PM2.5-induced autophagy of RPMI-2650 cells through AKT/mTOR pathway. Moreover, our in vivo study found that after administration of agomiR-338-3p in AR rats model, the expression of autophagy-related proteins decreased and nasal symptoms alleviated. In conclusion, this study revealed that miR-338-3p acts as an autophagy suppressor in PM2.5-exacerbated AR by directly targeting UBE2Q1 and affecting AKT/mTOR pathway.


Assuntos
MicroRNAs/genética , Mucosa Nasal/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Rinite Alérgica/prevenção & controle , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Poluentes Atmosféricos/análise , Animais , Autofagia/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Material Particulado/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Rinite Alérgica/etiologia , Rinite Alérgica/genética , Rinite Alérgica/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo
13.
Sci Rep ; 11(1): 6364, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737534

RESUMO

To understand the inflammatory microenvironment and microbiome factors for prognosis of chronic rhinosinusitis with polyps (CRSwNP), we explored the difference in characteristics of the microbiome of the nasal sinuses and inflammatory cytokines between recurrent and non-recurrent groups. We collected nasal secretions and polyp tissue from 77 CRSwNP patients. Then, we extracted microbial DNA from cotton swabs, performed high-throughput sequencing based on 16S rRNA to detect bacterial community composition, and analyzed cytokines such as IL-5, IL-8, IL-17a, IL-17e, IL-18, IL-27 and INF-gamma from polyp tissue using Luminex. The eosinophil and neutrophil cells in the peripheral blood and polyp tissue were counted. Postoperative follow-up of patients with CRSwNP for 1 year was conducted to record the recurrence of nasal polyps and analyze the correlation between the recurrence of nasal polyps and the characteristics of inflammatory cytokines, inflammatory cell count and nasal microbial diversity. After 1 year of follow-up, there were 12 recurrent patients, including 5 males and 7 females. Postoperative recurrence of nasal polyps was not significantly correlated with age, sex, asthma, allergic rhinitis or other allergic diseases in CRSwNP patients. In terms of the total nasal symptom score, the recurrent group was significantly higher than the non-recurrent group. In nasal polyp tissues, eosinophils (40.83/HP) and neutrophils (30.83/HP) in patients with CRSwNP in the recurrent group were significantly higher than those in the non-recurrent group (13.72/HP), and neutrophils (18.5/HP) were also significantly higher in the recurrent group than the non-recurrent group. The expression levels of IFN-, IL-17A, IL-17E and IL-18 were significantly higher in the recurrent group than in the non-recurrent group, and the positive rates were not different. In Southwest China, Enterobacteria and anaerobic bacteria may be correlated with the inflammatory pattern expression of nasal polyps. The neutrophil-mediated inflammatory response plays an important role in patients with CRSwNP in Southwest China and is correlated with nasal polyp recurrence. Recurrence of nasal polyps after endoscopic sinus surgery may be potentially associated with a reduced abundance of protective microorganisms and an increased number of pathogenic microorganisms.


Assuntos
Enterobacteriaceae/genética , Inflamação/genética , Microbiota/genética , Pólipos Nasais/microbiologia , Adulto , Bactérias/citologia , Bactérias/genética , China/epidemiologia , Enterobacteriaceae/patogenicidade , Eosinófilos/microbiologia , Eosinófilos/patologia , Feminino , Humanos , Inflamação/epidemiologia , Inflamação/microbiologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/microbiologia , Mucosa Nasal/patologia , Pólipos Nasais/epidemiologia , Pólipos Nasais/genética , Pólipos Nasais/patologia , Seios Paranasais/microbiologia , Seios Paranasais/patologia , Prognóstico , RNA Ribossômico 16S/genética , Rinite/epidemiologia , Rinite/genética , Rinite/microbiologia , Sinusite/epidemiologia , Sinusite/genética , Sinusite/microbiologia
14.
Sci Rep ; 11(1): 6206, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737667

RESUMO

High mobility group box 1 (HMGB1) has been known to involve in the pathogenesis of many inflammatory diseases. The aim of this study was to establish animal model of acute rhinosinusitis (ARS), and determine whether ethyl pyruvate (EP) attenuate inflammatory response of sinonasal mucosa by inhibiting HMGB1 in ARS animals. Thirty-six Sprague Dawley (SD) rat were used as follows: six normal controls without intervention (group 1); thirty rats were used for establishment of ARS rats model by nasal insertion of Merocel sponge, and model rats without any treatments (group 2), treated with nasal drops of sterile saline (group 3), 10 µl EP (group 4), and 20 µl EP (group 5), twice a day for 5 days, respectively. Bacterial culture was done regularly and the main bacterial strains were identified using matrix-assisted laser desorption/ionization time of flight mass spectrometry. HMGB1 expression in sinonasal mucosa was detected by immunohistochemistry and RT-PCR. Serum levels of HMGB1, IL-6, and TNF-α were determined by ELISA. Data from 29 of 36 rats that had completed research were analyzed. Bacterial colony formation unit (CFU) of nasal secretion was significantly higher in each group of ARS rats compared with controls (p < 0.001). ARS rats treated with EP had only slightly decreased CFU, but significantly attenuated inflammatory response of sinonasal mucosa and decreased HMGB1 expression compared to those treated with saline alone (p < 0.001). Serum levels of HMGB1, IL-6 and TNF-α were significantly higher in ARS rats compared to controls, and decreased by EP treatments (p < 0.001). Nasal sponge packing led to acute inflammatory response of nasal sinus in rats, and increased the expression of HMGB1, IL-6, and TNF-α. Nasal drops with EP could attenuate the inflammation of sinonasal mucosa through inhibiting the expression of HMGB1, IL-6 and TNF-α in ARS rats.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína HMGB1/genética , Mucosa Nasal/efeitos dos fármacos , Piruvatos/farmacologia , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Doença Aguda , Animais , Modelos Animais de Doenças , Formaldeído/administração & dosagem , Formaldeído/antagonistas & inibidores , Regulação da Expressão Gênica , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Álcool de Polivinil/administração & dosagem , Ratos , Ratos Sprague-Dawley , Rinite/induzido quimicamente , Rinite/genética , Rinite/patologia , Sinusite/induzido quimicamente , Sinusite/genética , Sinusite/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
Rhinology ; 59(3): 245-257, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33730750

RESUMO

BACKGROUND: The expression of metalloproteinases (MMPs) in chronic rhinosinusitis with nasal polyposis (CRSwNP) was reviewed in order to investigate their possible use as therapeutical targets and/or biomarkers. METHODOLOGY: The differences between CRSwNP and normal controls or CRS without NP, as well as the effects of various treatments on MMPs, tissue inhibitors of MMPs (TIMPs) and MMP/TIMP ratios were considered as primary outcomes. Additional factors reported to affect MMP expression levels were noted as secondary outcomes. Data regarding inflammatory subtypes, patients’ clinical characteristics, controls, laboratory method(s) and origin of samples were also pooled. Studies on 10 or fewer patients or on specimens other than nasal and serum were excluded. RESULTS: Forty-three studies were included. Tissue sample origin, allergic rhinitis, smoking, infection, medication intake and primary or recurrent disease should be considered as confounding factors for MMP levels. MMP-1 and -7 were consistently found to be significantly higher in CRSwNP patients than controls. CRSwNP endotypes with distinctly different inflammation patterns seem to present similar MMP-related remodelling patterns. CONCLUSIONS: The existing literature has revealed several population and methodology related confounding factors and remains inconclusive regarding the roles of MMPs in CRSwNP pathophysiology and their possible clinical usefulness as biomarkers and therapeutical targets.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Metaloproteinases da Matriz , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia
16.
Artigo em Chinês | MEDLINE | ID: mdl-33730810

RESUMO

Objective: To investigate the roles of hypoxic stimulation in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) by comparing the variation and differences of inflammatory factors secreted from epithelial cells of nasal polyps and normal nasal mucosa under hypoxic stimulation. Methods: Sixty-eight patients who were diagnosed with CRSwNP from June 2015 to January 2018 at China-Japan Union Hospital of Jilin University were analyzed, including 36 males and 32 females, aged (45.2±12.5) years. Nasal polyps mucosa was included in CRS-NP group and inferior turbinate mucosa was included in CRS-IT group. According to the degree of eosinophil infiltration in histopathologic results, each of these two groups was further divided into eosinophil infiltration and non-eosinophil infiltration as Eos-NP group (n=34), Non-Eos-NP group (n=34), Eos-IT group (n=20) and Non-Eos-IT group (n=20). The inferior turbinate mucosa of twenty-five patients who were diagnosed with cyst of paranasal sinus or deviation of nasal septum was classified as control group (n=25), including 14 males and 11 females, aged (42.8±10.2) years. The expression of interleukin 17A (IL-17A), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and hypoxia-inducible factor 1α (HIF-1α) in each group was analyzed by immunohistochemical staining. After 0, 24 and 48 h hypoxic stimulation, the secretion of IL-17A, IFN-γ, TNF-α in primary nasal mucosa epithelial cells of each group was tested by enzyme-linked immune sorbent assay (ELISA) experiment; the expression of HIF-1α was tested by immunofluorescent staining and imaging and Western blot. SPSS 17.0 software and two-way ANOVA were used for statistical analysis. Results: Immunohistochemical staining showed that the expression of IL-17A and TNF-α was much higher in control group (optical density (OD) value was 0.37±0.03, 0.53±0.02, respectively) and the expression of IFN-γ and HIF-1α was much higher in Eos-IT group (OD value was 0.47±0.03, 0.39±0.02, respectively). The secretion of IL-17A and TNF-α was much lower in control group than that in other groups under normal condition. After 48 h hypoxic stimulation, the secretion of IL-17A and TNF-α was much higher in control group compared with other groups. The secretion of IFN-γ in Eos-NP group was much higher than that in control group under normal condition ((13.7±1.3) pg/ml vs (11.1±1.6) pg/ml, P<0.05). After 48 h hypoxic stimulation, there was no difference of IFN-γ between control group and Eos-NP group. The expression of HIF-1α decreased in Eos-NP group and Non-Eos-NP group while increased in CRS-IT group and control group upon prolonged exposure to hypoxia. HIF-1α was mostly located at cytoplasm of epithelial cells in control and CRS-IT group while mainly located at nucleus of epithelial cells in CRS-NP group. Conclusions: The secretion of IL-17A, TNF-α, IFN-γ and the expression of HIF-1α show significant difference between normal nasal mucosa, polyps and inferior turbinate of CRSwNP under hypoxic stimulation, presenting different subcellular localization. This illustrates the proteins above are involved in transcription and regulation of the gene responsible for the pathogenesis of CRSwNP.


Assuntos
Pólipos Nasais , Rinite , Adulto , China , Doença Crônica , Células Epiteliais , Feminino , Humanos , Hipóxia/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite/patologia
17.
J Vis Exp ; (168)2021 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-33720120

RESUMO

The early interactions between the nasal epithelial layer and the innate immune cells during viral infections remains an under-explored area. The significance of innate immunity signaling in viral infections has increased substantially as patients with respiratory infections who exhibit high innate T cell activation show a better disease outcome. Hence, dissecting these early innate immune interactions allows the elucidation of the processes that govern them and may facilitate the development of potential therapeutic targets and strategies for dampening or even preventing early progression of viral infections. This protocol details a versatile model that can be used to study early crosstalk, interactions, and activation of innate immune cells from factors secreted by virally infected airway epithelial cells. Using an H3N2 influenza virus (A/Aichi/2/1968) as the representative virus model, innate cell activation of co-cultured peripheral blood mononuclear cells (PBMCs) has been analyzed using flow cytometry to investigate the subsets of cells that are activated by the soluble factors released from the epithelium in response to the viral infection. The results demonstrate the gating strategy for differentiating the subsets of cells and reveal the clear differences between the activated populations of PBMCs and their crosstalk with the control and infected epithelium. The activated subsets can then be further analyzed to determine their functions as well as molecular changes specific to the cells. Findings from such a crosstalk investigation may uncover factors that are important for the activation of vital innate cell populations, which are beneficial in controlling and suppressing the progression of viral infection. Furthermore, these factors can be universally applied to different viral diseases, especially to newly emerging viruses, to dampen the impact of such viruses when they first circulate in naïve human populations.


Assuntos
Imunidade Inata , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia , Influenza Humana/virologia , Modelos Biológicos , Células 3T3 , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Impedância Elétrica , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Alimentadoras/citologia , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Camundongos , Mitomicina/farmacologia , Mucina-5AC/metabolismo , Mucosa Nasal/patologia , Tubulina (Proteína)/metabolismo
18.
Laryngoscope ; 131(8): 1798-1804, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33616259

RESUMO

OBJECTIVES/HYPOTHESIS: The routine practices of examining submucosal lesions are not suitable for deep lesions. Therefore, we evaluated the efficacy of non-real-time image-guided transnasal endoscopic fine-needle aspiration biopsy (FNAB) in diagnosing nasopharyngeal carcinoma (NPC) with submucosal lesions. STUDY DESIGN: The effectiveness evaluation of diagnostic methods. METHODS: Fifty suspected NPC patients who failed in conventional biopsies were enrolled in this study. The efficacy, maneuverability, and safety of FNAB in diagnosing these intractable cases were evaluated. RESULTS: The definitive diagnostic results of these 50 patients were NPC (34/50, 68.0%), nasopharyngeal necrosis (1/50, 2.0%), nasopharyngeal mucositis (12/50, 24.0%), and other cancers (3/50, 6.0%), respectively. The results of the diagnostic efficacy of FNAB were sensitivity, 89.2%; specificity, 100.0%; positive predictive value, 100.0%; negative predictive value, 76.5%; and accuracy, 92.0%, respectively. The area under the receiver operating characteristic curves was 0.946 (95% confidence interval = 0.884-1.00, P < .001). No severe complications occurred after FNAB. CONCLUSIONS: FNAB can improve the diagnostic efficiency of NPC occurring in the submucosal space. It can be an additional option for routine nasopharyngeal biopsy and is worthy of clinical application. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1798-1804, 2021.


Assuntos
Biópsia por Agulha Fina/métodos , Endoscopia/métodos , Biópsia Guiada por Imagem/métodos , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Mucosa Nasal/cirurgia , Nasofaringe/patologia , Nasofaringe/cirurgia , Valor Preditivo dos Testes , Curva ROC , Adulto Jovem
19.
Ann Otol Rhinol Laryngol ; 130(9): 1069-1077, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33576238

RESUMO

OBJECTIVES: Previous work showed that higher polyp mast cell load correlated with worse postoperative endoscopic appearance in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Polyp epithelial mast cells showed increased expression of T-cell/transmembrane immunoglobulin and mucin domain protein 3 (TIM-3), a receptor that promotes mast cell activation and cytokine production. In this study, CRSwNP patients were followed post-operatively to investigate whether mast cell burden or TIM-3 expression among mast cells can predict recalcitrant disease. METHODS: Nasal polyp specimens were obtained via functional endoscopic sinus surgery (FESS) and separated into epithelial and stromal layers via enzymatic digestion. Mast cells and TIM-3-expressing mast cells were identified via flow cytometry. Mann-Whitney U tests and Cox proportional hazard models assessed whether mast cell burden and TIM-3 expression were associated with clinical outcomes, including earlier recurrence of polypoid edema and need for treatment with steroids. RESULTS: Twenty-three patients with CRSwNP were studied and followed for 6 months after undergoing FESS. Higher mast cell levels were associated with earlier recurrence of polypoid edema: epithelial HR = 1.283 (P = .02), stromal HR = 1.103 (P = .02). Percent of mast cells expressing TIM-3 in epithelial or stromal layers was not significantly associated with earlier recurrence of polypoid edema. Mast cell burden and TIM-3+ expression were not significantly associated with need for future treatment with steroids post-FESS. CONCLUSIONS: Mast cell load in polyp epithelium and stroma may predict a more refractory postoperative course for CRSwNP patients. The role of TIM-3 in the chronic inflammatory state seen in CRSwNP remains unclear.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Mastócitos/patologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia , Adulto , Contagem de Células , Doença Crônica , Endoscopia , Feminino , Citometria de Fluxo , Humanos , Masculino , Mastócitos/metabolismo , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/metabolismo , Pólipos Nasais/cirurgia , Procedimentos Cirúrgicos Nasais , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Rinite/metabolismo , Rinite/cirurgia , Teste de Desfecho Sinonasal , Sinusite/metabolismo , Sinusite/cirurgia
20.
Laryngoscope ; 131(9): 1952-1957, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33616224

RESUMO

OBJECTIVES/HYPOTHESIS: To assess the long-term (12-24 months) safety and effectiveness of cryoablation of the posterior nasal nerve as treatment for chronic rhinitis. STUDY DESIGN: A multicenter, prospective, single-arm clinical study. METHODS: The study was conducted from February 2017 to April 2020. Study endpoints included change from baseline in the reflective Total Nasal Symptom Score (rTNSS), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), physician assessment of improvement using the Clinical Global Impression-Improvement (CGI-I), and the incidence of treatment-related adverse events. RESULTS: Ninety-one participants completed the study through the initial 12-month study period. Sixty-two participants consented to the long-term follow-up with 57 completing the 24-month follow-up. Significant improvements in the total rTNSS were reflected in a median change from baseline of -3.0 or -4.0 at all timepoints (P < .001). Greater than 80.0% of participants achieved the minimum clinically important difference (MCID) of improvement by ≥1 point on the rTNSS at all follow-ups. Total RQLQ scores indicated significant improvement (P < .0001) in quality of life. Over 77% of participants achieved the MCID (≥0.5 points) for the total RQLQ score. According to the CGI-I, ≥83.0% experienced improvement at all but the 12-month visit (61.9%). One participant experienced two treatment-related serious adverse events (epistaxis and retained pledget). A total of 29 nonserious treatment-related AEs were reported in 23 participants; most events were transient and resolved with little to no intervention. CONCLUSIONS: Cryotherapy significantly and clinically improves rhinitis symptoms and quality of life with outcomes that are durable through 24 months after treatment. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1952-1957, 2021.


Assuntos
Criocirurgia/efeitos adversos , Mucosa Nasal/inervação , Rinite/psicologia , Rinite/cirurgia , Adulto , Idoso , Doença Crônica , Criocirurgia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Estudos Prospectivos , Qualidade de Vida , Rinite/diagnóstico , Segurança , Inquéritos e Questionários/estatística & dados numéricos , Resultado do Tratamento
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