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1.
Life Sci ; 271: 119218, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33592198

RESUMO

AIM: We aimed to discover whether group 2 innate lymphoid cells (ILC2s) and cytokines in nasal lavage fluid could be used to predict eosinophilic infiltration in mice with eosinophilic chronic rhinosinusitis (ECRS). METHODS: Ten mice were divided into two groups. The ECRS group received an intranasal challenge of Aspergillus oryzae protease (AP) and ovalbumin (OVA) to establish disease. A control group received intranasal phosphate-buffered saline. Histopathology of nasal cavities and paranasal sinuses, and cytokine and ILC2s levels in nasal lavage fluid were analyzed and compared between the ECRS and control mouse groups. KEY FINDINGS: ILC2s numbers were not significantly higher in the nasal lavage fluid of the ECRS group mice compared with those of the control group. Eotaxin/chemokine (CC motif) ligand 11 (CCL11) levels were significantly higher in the nasal lavage fluid of mice in the ECRS group compared with those in the control group. However, no statistical differences were seen in the classic proinflammatory cytokines, IL-33, IL-25, and thymic stromal thymopoietin (TSLP), or the classic type 2 cytokines, IL-4, IL-5, and IL-13 between groups. SIGNIFICANCE: Eotaxin/CCL11 levels in nasal lavage fluid rather than that of ILC2s and classic proinflammatory and type 2 cytokines were significantly higher in ECRS mice compared with control ones. Eotaxin/CCL11 showed diagnostic and therapeutic value; however, more studies are needed to test and verify its value.


Assuntos
Quimiocina CCL11/metabolismo , Eosinofilia/metabolismo , Imunidade Inata/fisiologia , Líquido da Lavagem Nasal , Sinusite/metabolismo , Animais , Quimiocina CCL11/imunologia , Doença Crônica , Eosinofilia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Líquido da Lavagem Nasal/imunologia , Valor Preditivo dos Testes , Sinusite/imunologia , Sinusite/patologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-33338738

RESUMO

Current literature implicates arachidonic acid-derived leukotrienes and prostaglandins in the pathogenesis of chronic rhinosinusitis. However, other omega-3 and omega-6 derived lipid mediators, such as specialized pro-resolving mediators (SPMs), may also be important in chronic inflammatory disorders of the upper airway. We hypothesize that SPMs differ among CRS subtypes compared to controls and in relation to sinonasal microbiota. Ethmoid sinus tissue and middle meatal swabs were collected from a convenience sample of 66 subjects, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. Resolvin D2 was elevated in both CRSwNP (p = 0.00076) and CRSsNP (p = 0.030) compared with non-CRS controls. Lipoxin A4 was significantly increased in CRSwNP compared with CRSsNP (p = 0.000033) and controls (p = 0.044). Cigarette smoking was associated with significantly lower concentrations of several 15-lipoxygenase metabolites including resolvin D1 (p = 0.0091) and resolvin D2 (p = 0.0097), compared with never-smokers. Several of the lipid compounds also correlated with components of the sinonasal mucosal microbiota, including bacterial pathogens such as Pseudomonas aeruginosa. These data suggest that dysfunctional lipid mediator pathways in CRS extend beyond the traditional descriptions of leukotrienes and prostaglandins and include SPMs. Furthermore, dysregulated SPM signaling may contribute to persistent inflammation and bacterial colonization in CRS.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Mediadores da Inflamação/metabolismo , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Adulto , Doença Crônica , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Fumar/metabolismo
4.
Clin Immunol ; 223: 108659, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352294

RESUMO

Endoplasmic reticulum (ER) stress results in the activation of the unfolded protein response (UPR), a process that is involved in the pathogenesis of many inflammatory diseases. However, the role of ER stress in chronic rhinosinusitis with nasal polyps (CRSwNP) has yet to be elucidated. In this study, we found that the protein expression levels of a range of ER stress regulators, including p-PERK, ATF4, ATF6 and XBP1s, were significantly increased in CRSwNP compared to controls. Importantly, the expression of ATF4 and XBP1s was positively correlated with heightened inflammation in CRSwNP. In human nasal epithelial cells, the ER stress inducer tunicamycin (TM) could potentiate Toll-like receptors (TLRs) induced proinflammatory cytokines production. Furthermore, we found that the silencing of XBP1, but not ATF4 or ATF6, abrogated the proinflammatory effect of TM. Mechanistically, ER stress did not affect the NF-κB, MAPK or IRF3 signaling pathways. However, the ER stress regulator XBP1s was able to bind directly to the promoter region of inflammatory genes to modulate gene transcription. Besides, the commensal bacteria Staphylococcus aureus and several inflammatory factors, such as IL4, IL13, IL17 and IFNγ, could induce ER stress in epithelial cells. Collectively, ER stress plays a crucial role in facilitating TLR-induced inflammation. Targeting XBP1 can inhibit the inflammatory response, thus offering a potential approach to treat CRSwNP.


Assuntos
Estresse do Retículo Endoplasmático/imunologia , Inflamação/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Adolescente , Adulto , Idoso , Células Cultivadas , Doença Crônica , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , RNA Interferente Pequeno/genética , Transdução de Sinais , Proteína 1 de Ligação a X-Box/genética , Adulto Jovem
5.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322143

RESUMO

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use as a therapeutic option against severe airway diseases. Airway mucosa acts as a relative barrier, modulating antigenic stimulation and responding to environmental pathogen exposure with a specific, self-limited response. In severe asthma and/or CRS, genome-environmental interactions lead to dysbiosis, aggravated inflammation, and disease. In healthy conditions, single or combined type 1, 2, and 3 immunological response pathways are invoked, generating cytokine, chemokine, innate cellular and T helper (Th) responses to eliminate viruses, helminths, and extracellular bacteria/fungi, correspondingly. Although the pathomechanisms are not fully known, the majority of severe airway diseases are related to type 2 high inflammation. Type 2 cytokines interleukins (IL) 4, 5, and 13, are orchestrated by innate lymphoid cell (ILC) and Th subsets leading to eosinophilia, immunoglobulin E (IgE) responses, and permanently impaired airway damage. Monoclonal antibodies can bind or block key parts of these inflammatory pathways, resulting in less inflammation and improved disease control.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/imunologia , Inflamação/imunologia , Transtornos Respiratórios/imunologia , Rinite Alérgica/imunologia , Sinusite/imunologia , Asma/tratamento farmacológico , Citocinas/metabolismo , Humanos , Imunidade Inata , Inflamação/metabolismo , Transtornos Respiratórios/tratamento farmacológico , Rinite Alérgica/tratamento farmacológico , Sinusite/tratamento farmacológico , Sinusite/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia
6.
Nat Commun ; 11(1): 5453, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116139

RESUMO

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/patologia , Expressão Gênica/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Sistema Respiratório/patologia , Fatores Etários , Cílios/metabolismo , Infecções por Coronavirus/virologia , Células Endoteliais , Células Caliciformes/metabolismo , Humanos , Pulmão/patologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Fatores Sexuais , Sinusite/metabolismo , Fumar
7.
Am J Respir Cell Mol Biol ; 63(5): 707-709, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32857620
8.
Artigo em Chinês | MEDLINE | ID: mdl-32610404

RESUMO

Objective: To investigate the expression and cellular provenance of interleukin 17A (IL-17A) in non-eosinophilic chronic rhinosinusitis with nasal polyps (nECRSwNP), and to analyze the possible reasons for its different expression. Methods: Samples were collected from 14 patients with eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) and 28 patients with nECRSwNP, who underwent functional endoscopic sinus surgery in the Third Affiliated Hospital of Sun Yat-sen University from January 2017 to May 2018, including 33 males and 9 females, with the age ranging from 18 to 65 years old. Enzyme linked immune sorbent assay (ELISA) and flow cytometry were used to investigate the expression and cellular origins of IL-17A in the nasal tissue of ECRSwNP and nECRSwNP groups. Then the difference of quantity and differentiation ability of the major cells producing IL-17A between ECRSwNP and nECRSwNP groups were analyzed by flow cytometry. Finally, the expressions of IL-6, transforming growth factor-ß(TGF-ß), and IL-23, which were considered as the important factors in promoting Th17/Tc17 differentiation in CRSwNP and their correlation with IL-17A, were analyzed by ELISA. Statistical analysis was performed using IBM SPSS 20. Results: The IL-17A protein levels and IL-17A(+)lymphocyte percentages were higher in nECRSwNP group compared with that of the ECRSwNP group (158.56 (167.76) pg/ml (M(QR)) vs. 9.42 (11.33) pg/ml, 10.21%±1.54% (x±s) vs. 3.93%±0.80%, Z=2.95, t=3.62, all P<0.01). Tc17 cells (CD8(+)T cells producing IL-17A) and Th17 cells (CD4(+)T cells producing IL-17A) were major IL-17A producers in both ECRSwNP and nECRSwNP group. Further analysis revealed that there was no significant difference in quantity of CD8(+)and CD4(+)T cells between ECRSwNP and nECRSwNP group, but the differentiation ability about CD8(+)and CD4(+)T cells differentiating into Tc17 and Th17 in nECRSwNP group was stronger than that in ECRSwNP. The high expressions of IL-6 and TGF-ß, which were considered as the important factors in promoting Th17/Tc17 differentiation were also found in nECRSwNP group compared with ECRSwNP (56.07 (234.25) pg/ml vs. 8.27 (12.51) pg/ml, (5.44±0.34) pg/ml vs. (4.17±0.22) pg/ml, Z=2.426, t=2.29, all P<0.05). But the difference in expression of IL-23 was not significant difference between the two groups. Moreover, the expression of IL-17A showed significantly positive correlation with IL-6 (r=0.615, P=0.009). No positive correlation between IL-17A and TGF-ß or IL-23 was observed. Conclusions: The expression of IL-17A in nasal mucosa of nECRSwNP patients is significantly higher than that of ECRSwNP, which is due to the increase of expression and differentiation of Tc17/Th17 cells. IL-17A shows positive correlation with IL-6 in CRSwNP, which is the important factor in promoting Th17/Tc17 differentiation.


Assuntos
Interleucina-17 , Pólipos Nasais , Rinite , Sinusite , Adolescente , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Rinite/metabolismo , Rinite/patologia , Sinusite/metabolismo , Sinusite/patologia , Adulto Jovem
9.
Am J Otolaryngol ; 41(5): 102587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32516657

RESUMO

BACKGROUND: Olfactory dysfunction secondary to chronic rhinosinusitis (CRS) has been highly associated with impaired quality of life. Asian CRS patients showed a distinct inflammatory profile, with less type 2 endotype compared with European and North American. This study aimed to explore the pattern of the inflammatory cytokines in CRS patients from China and their association with olfactory function. METHODS: Institutional review board-approved prospective study in which the olfactory function of 71 CRS patients was assessed with Sniffin' Sticks before the nasal endoscopic surgery. A set of cytokines and inflammatory mediators including type 1 and type 2 inflammatory cytokines were measured in nasal mucus by using a multiplex flow cytometric bead assay (CBA). Baseline characteristics in CRS patients were collected and the Spearman r statistic was performed to assess the association of olfactory function with cytokines and inflammatory mediators. RESULTS: A total of 71 nasal mucus samples of CRS patients, including 25 chronic rhinosinusitis without nasal polyposis (CRSsNP) patients and 46 chronic rhinosinusitis with nasal polyposis (CRSwNP) patients, were evaluated in this study. The nasal mucus levels of type 1 inflammatory cytokine IFN-γ (interferon-γ), type 2 inflammatory cytokines including IL-4, IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) and anti-inflammatory cytokine IL-10 were significantly and inversely correlated with olfactory function in total patients with CRS (r = -0.308, p = 0.009; r = -0.250, p = 0.036; r = -0.399, p = 0.001; r = -0.269, p = 0.023; r = -0.273, p = 0.021, respectively). In CRSsNP, the olfactory function was inversely correlated with levels of type 1 inflammatory cytokine TNF-α (tumor necrosis factor-α) (r = -0.637, p = 0.001) and IL-10 (r = -0.468, p = 0.018). Nevertheless, the olfactory function in CRSwNP was inversely correlated with type 2 inflammatory cytokines including IL-4 (r = -0.303, p = 0.041) and IL-5 (r = -0.383, p = 0.009). CONCLUSION: Both type 1 and type 2 inflammatory cytokines may contribute to the pathogenesis of CRS-associated olfactory dysfunction in the Chinese population.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Rinite/etiologia , Rinite/fisiopatologia , Sinusite/etiologia , Sinusite/fisiopatologia , Olfato , Adulto , Grupo com Ancestrais do Continente Asiático , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rinite/metabolismo , Sinusite/metabolismo
10.
J Allergy Clin Immunol ; 145(3): 740-750, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32145873

RESUMO

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases worldwide. It is a heterogeneous disease, and geographical or ethnic differences in inflammatory pattern in nasal mucosa are major issues. Tissue eosinophilia in CRS is highly associated with extensive sinus disease, recalcitrance, and a higher nasal polyp (NP) recurrence rate after surgery. The prevalence of eosinophilic CRS (ECRS) is increasing in Asian countries within the last 2 decades, and this trend appears to be occurring across the world. International consensus criteria for ECRS are required for the accurate understanding of disease pathology and precision medicine. In a multicenter large-scale epidemiological survey, the "Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis study," ECRS was definitively defined when the eosinophil count in nasal mucosa is greater than or equal to 70 eosinophils/hpf (magnification, ×400), and this study proposed an algorithm that classifies CRS into 4 groups according to disease severity. The main therapeutic goal with ECRS is to eliminate or diminish the bulk of NP tissue. NPs are unique abnormal lesions that grow from the lining of the nasal and paranasal sinuses, and type 2 inflammation plays a critical role in NP development in patients with ECRS. An imbalance between protease and endogenous protease inhibitors might play a pivotal role in the initiation and exacerbation of type 2 inflammation in ECRS. Intraepithelial mast cells in NPs, showing a tryptase+, chymase- phenotype, may also enhance type 2 inflammation. Intense edema and reduced fibrosis are important histological features of eosinophilic NPs. Mucosal edema mainly consists of exuded plasma protein, and excessive fibrin deposition would be expected to contribute to the retention of proteins from capillaries and thereby perpetuate mucosal edema that may play an etiological role in NPs. Upregulation of the coagulation cascade and downregulation of fibrinolysis strongly induce abnormal fibrin deposition in nasal mucosa, and type 2 inflammation plays a central role in the imbalance of coagulation and fibrinolysis.


Assuntos
Fibrina/metabolismo , Inflamação/imunologia , Inflamação/patologia , Pólipos Nasais/imunologia , Pólipos Nasais/patologia , Doença Crônica , Eosinófilos/imunologia , Eosinófilos/patologia , Humanos , Imunidade Inata/imunologia , Inflamação/metabolismo , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Pólipos Nasais/metabolismo , Rinite/imunologia , Rinite/metabolismo , Rinite/patologia , Sinusite/imunologia , Sinusite/metabolismo , Sinusite/patologia
11.
J Allergy Clin Immunol ; 145(2): 550-562, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32035607

RESUMO

BACKGROUND: Airway eosinophilia is a prominent feature of asthma and chronic rhinosinusitis (CRS), and the endothelium plays a key role in eosinophil trafficking. To date, microRNA-1 (miR-1) is the only microRNA known to be regulated in the lung endothelium in asthma models. OBJECTIVE: We sought to determine the role of endothelial miR-1 in allergic airway inflammation. METHODS: We measured microRNA and mRNA expression using quantitative RT-PCR. We used ovalbumin and house dust mite models of asthma. Endothelium-specific overexpression of miR-1 was achieved through lentiviral vector delivery or induction of a transgene. Tissue eosinophilia was quantified by using Congo red and anti-eosinophil peroxidase staining. We measured eosinophil binding with a Sykes-Moore adhesion chamber. Target recruitment to RNA-induced silencing complex was assessed by using anti-Argonaute2 RNA immunoprecipitation. Surface P-selectin levels were measured by using flow cytometry. RESULTS: Serum miR-1 levels had inverse correlations with sputum eosinophilia, airway obstruction, and number of hospitalizations in asthmatic patients and sinonasal tissue eosinophilia in patients with CRS. IL-13 stimulation decreased miR-1 levels in human lung endothelium. Endothelium-specific overexpression of miR-1 reduced airway eosinophilia and asthma phenotypes in murine models and inhibited IL-13-induced eosinophil binding to endothelial cells. miR-1 recruited P-selectin, thymic stromal lymphopoietin, eotaxin-3, and thrombopoietin receptor to the RNA-induced silencing complex; downregulated these genes in the lung endothelium; and reduced surface P-selectin levels in IL-13-stimulated endothelial cells. In our asthma and CRS cohorts, miR-1 levels correlated inversely with its target genes. CONCLUSION: Endothelial miR-1 regulates eosinophil trafficking in the setting of allergic airway inflammation. miR-1 has therapeutic potential in asthmatic patients and patients with CRS.


Assuntos
Asma/imunologia , Quimiotaxia de Leucócito/imunologia , MicroRNAs/imunologia , MicroRNAs/metabolismo , Rinite Alérgica Perene/imunologia , Sinusite/imunologia , Animais , Asma/metabolismo , Asma/patologia , Células Endoteliais/metabolismo , Eosinófilos , Humanos , Camundongos , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/metabolismo , Eosinofilia Pulmonar/patologia , Rinite Alérgica Perene/metabolismo , Rinite Alérgica Perene/patologia , Sinusite/metabolismo , Sinusite/patologia
12.
J Allergy Clin Immunol ; 145(3): 843-854.e4, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035658

RESUMO

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.


Assuntos
Antígenos CD/metabolismo , Eosinofilia/metabolismo , Rinite/metabolismo , Semaforinas/metabolismo , Sinusite/metabolismo , Adulto , Animais , Antígenos CD/imunologia , Antígenos CD/farmacologia , Doença Crônica , Eosinofilia/imunologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Proteínas Recombinantes/farmacologia , Rinite/imunologia , Semaforinas/imunologia , Semaforinas/farmacologia , Sinusite/imunologia , Migração Transendotelial e Transepitelial/efeitos dos fármacos
13.
Int Forum Allergy Rhinol ; 10(1): 15-22, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31645085

RESUMO

BACKGROUND: Mucus cytokines have been linked to baseline metrics of quality of life and olfactory function in patients with chronic rhinosinusitis (CRS). However, their potential utility in predicting postoperative outcomes has not been assessed. Therefore, in this study we evaluated the role of mucus cytokines in predicting 22-item Sino-Nasal Outcomes Test (SNOT-22) scores after endoscopic sinus surgery (ESS) in a prospective cohort of CRS patients. METHODS: One hundred forty-seven patients with CRS electing surgical therapy were enrolled in a longitudinal cohort study. Mucus was collected intraoperatively from the middle meatus and tested for interleukin (IL)-1ß, IL-2, -4, -5, -6, -7,- 8, -9, -10, -12, -13, -17A, and -21; tumor necrosis factor (TNF)-α; interferon-γ; eotaxin; and RANTES (regulated-on-activation, normal T-cell expressed and secreted) expression using a multiplex flow-cytometric bead assay. Sixty-two patients were followed postoperatively (average, 10.2 months) with baseline and follow-up SNOT-22 surveys. Stepwise multivariate linear regression was used to model relationships between baseline cytokines, phenotype, and average postoperative SNOT-22 total and domain scores. A machine learning approach using a random forest algorithm was also used to investigate potential nonlinear relationships. RESULTS: IL-5 was an independent predictor of postoperative total SNOT-22 improvement (ß = -8.8, p < 0.0001), whereas IL-2 levels predicted postoperative worsening (ß = 6.97, p = 0.0015). Similar relationships were also seen for postoperative SNOT-22 domain scores. The overall model was also noted to be significant fit for the data (adjusted R2 = 0.398, p < 0.0001). The random forest model similarly identified IL-5, TNF-α, IL-13, and IL-2 as major predictors of postoperative SNOT-22 scores. CONCLUSION: Mucus cytokine profiles may help identify CRS patients who are likely to obtain postoperative improvement after ESS.


Assuntos
Citocinas/metabolismo , Endoscopia , Mucosa Nasal/metabolismo , Rinite/cirurgia , Sinusite/cirurgia , Adulto , Idoso , Biomarcadores/metabolismo , Doença Crônica , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Seios Paranasais/patologia , Seios Paranasais/cirurgia , Prognóstico , Estudos Prospectivos , Rinite/metabolismo , Rinite/patologia , Teste de Desfecho Sinonasal , Sinusite/metabolismo , Sinusite/patologia , Adulto Jovem
15.
Am J Respir Cell Mol Biol ; 62(1): 23-34, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31194918

RESUMO

No previously suggested biomarkers of nasal mucosal inflammation have been practically applied in clinical fields, and nasal epithelium-derived secreted proteins as biomarkers have not specifically been investigated. The goal of this study was to identify secreted proteins that dynamically change during the differentiation from basal cells to fully differentiated cells and examine whether nasal epithelium-derived proteins can be used as biomarkers of nasal mucosal inflammation, such as chronic rhinosinusitis. To achieve this goal, we analyzed two secretomes using the isobaric tag for relative and absolute quantification technique. From in vitro secretomes, we identified the proteins altered in apical secretions of primary human nasal epithelial cells according to the degree of differentiation; from in vivo secretomes, we identified the increased proteins in nasal lavage fluids obtained from patients 2 weeks after endoscopic sinus surgery for chronic sinusitis. We then used a parallel approach to identify specific biomarkers of nasal mucosal inflammation; first, we selected apolipoprotein E as a nasal epithelial cell-derived biomarker through screening proteins that were upregulated in both in vitro and in vivo secretomes, and verified highly secreted apolipoprotein E in nasal lavage fluids of the patients by Western blotting. Next, we selected periostin as an inflammatory mediator-inducible biomarker from in vivo secretomes, the secretion of which was not induced under in vitro culture conditions. We demonstrated that those two nasal epithelium-derived proteins are possible biomarkers of nasal mucosal inflammation.


Assuntos
Apolipoproteínas E/metabolismo , Biomarcadores/metabolismo , Moléculas de Adesão Celular/metabolismo , Inflamação/metabolismo , Mucosa Nasal/metabolismo , Doença Crônica , Células Epiteliais/metabolismo , Feminino , Humanos , Masculino , Líquido da Lavagem Nasal , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo
16.
Laryngoscope ; 130(5): E289-E297, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31294840

RESUMO

OBJECTIVE: Carbocisteine (CCis), a mucoactive agent, is used to improve the symptoms of sinonasal diseases. However, the effect of CCis on nasal ciliary beating remains uncertain. We examined the effects of CCis on ciliary beat distance (CBD, an index of amplitude), and ciliary beat frequency (CBF) in ciliated human nasal epithelial cells (cHNECs) in primary culture. METHODS: The cHNECs were prepared from the nasal tissue resected from patients required surgery for chronic sinusitis (CS) or allergic rhinitis (AR). CBD and CBF were measured using videomicroscopy equipped with a high-speed camera. RESULTS: CCis increased CBD by 30%, but not CBF, and decreased intracellular Cl- concentration ([Cl- ]i ) in cHNECs. The CCis' actions were mimicked by the Cl- -free NO3 - solution. In contrast, prior treatment of NPPB (20 µM) or CFTR(inh)-172 (1 µM), which increased [Cl- ]i by 20%, decreased CBF by 10% and CBD by 25% and inhibited the CCis' actions. However, prior treatment of T16Ainh-A01 (10 µM) did not inhibit the CCis' actions, although it decreased [Cl- ]i by 10% and CBD by 15%. Thus, CCis stimulates Cl- channels including cystic fibrosis transmembrane conductance regulator (CFTR). Moreover, CCis enhanced the transport of microbeads driven by the beating cilia in cHNECs. The CCis actions were similar in cHNECs from both types of pateints. CONCLUSION: CCis increased CBD by 30% in cHNECs via an [Cl- ]i decrease stimulated by activation of Cl- channels, including CFTR. CCis may stimulate nasal mucociliary clearance by increasing CBD in patients contracting CS or AR. LEVEL OF EVIDENCE: NA. Laryngoscope, 130:E289-E297, 2020.


Assuntos
Carbocisteína/farmacologia , Cílios/efeitos dos fármacos , Depuração Mucociliar/efeitos dos fármacos , Mucosa Nasal/diagnóstico por imagem , Sinusite/tratamento farmacológico , Células Cultivadas , Cílios/metabolismo , Cílios/patologia , Células Epiteliais/efeitos dos fármacos , Humanos , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Transdução de Sinais , Sinusite/metabolismo , Sinusite/patologia
18.
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 54(11): 850-856, 2019 Nov 07.
Artigo em Chinês | MEDLINE | ID: mdl-31795547

RESUMO

Objective: To explore the expression of amphiregulin (AREG) in nasal polyps patients with different degrees of eosinophil infiltration, and to analyze the correlation between AREG and tissue remodeling. Methods: Forty-eight patients underwent endoscopic sinus surgery in the Department of Otorhinolaryngology Head and Neck Surgery, Remin Hospital, Wuhan University from July 2017 to August 2018 were recruited, including 40 males and 8 females, aged from 16 to 60 years old. The subjects were divided into three groups: control group (n=14), eosinophilic chronic sinusitis with nasal polyps (ECRSwNP) group (n=19) and noneosinophilic chronic rhinosinusitis with nasal polyps (non-ECRSwNP) group (n=15). The relative expression of AREG in nasal mucosa was detected by Western blot assay and immunohistochemical staining. Tissue remodeling was detected by HE staining, AB-PAS staining and Masson staining. Kruskal-Wallis test was used for comparison among multiple groups, and Spearman correlation analysis was conducted between the expression level of AREG and the related indexes of tissue remodeling. Results: The expression of AREG in ECRSwNP group was significantly higher than that in non-ECRSwNP group and control group (median protein expression of Western blot was 1.592 vs 0.617 vs0.582, all P<0.05). The degree of epithelial injury and goblet cell metaplasia in ECRSwNP group was significantly higher than that in control group (all P<0.05), the percentage of collagen fibrosis area in ECRSwNP group was significantly lower than that in control group (P=0.01). In chronic rhinosinusitis with nasal polyps (CRSwNP) patients, the area of mucous glands was negatively correlated with the expression of AREG (r=-0.616, P<0.05), and the percentage of collagen fibrosis area was negatively correlated with the expression of AREG (r=-0.738, P<0.05). Conclusion: The expression of AREG is higher in ECRSwNP patients, which is related to the process of tissue remodeling.


Assuntos
Anfirregulina/biossíntese , Eosinófilos/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Adolescente , Adulto , Doença Crônica , Feminino , Fibrose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Mucosa Nasal/cirurgia , Pólipos Nasais/patologia , Pólipos Nasais/cirurgia , Rinite/patologia , Rinite/cirurgia , Sinusite/patologia , Sinusite/cirurgia , Adulto Jovem
19.
Braz. j. otorhinolaryngol. (Impr.) ; 85(6): 760-765, Nov.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1055517

RESUMO

Abstract Introduction: Chronic rhinosinusitis with nasal polyps is a heterogeneous disease and appropriate diagnostic algorithms in individual cases are necessary for effective medical treatment. Objective: The purpose of this study was to clarify the relationship between the pendrin expression of nasal polyps and clinical and pathological characteristic features of eosinophilic chronic rhinosinusitis. Methods: A total of 68 patients were classified into eosinophilic chronic rhinosinusitis or non-eosinophilic chronic rhinosinusitis groups according to the degree of eosinophilic infiltration into the nasal polyps. Clinical, hematological, and immunohistochemical analyses were performed and statistically compared between both groups. Results: Thirty-eight were classified into eosinophilic chronic rhinosinusitis and 30 into non-eosinophilic chronic rhinosinusitis groups. There were no significant differences in age distribution, sex ratio, prevalence of asthma, or any other complications between the groups. The mean Lund-Mackay score and the number of serum eosinophils was significantly higher in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis groups. The pendrin expression was more frequently detected in the epithelial surface layer of nasal polyps in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis groups. In addition, mucin 5AC was more widely expressed in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis. Conclusion: Increased expression of pendrin and mucin 5AC in the nasal polyps would be associated with development of eosinophilic chronic rhinosinusitis. This finding could allow the development of a novel therapeutic agent targeted specifically to patients with eosinophilic chronic rhinosinusitis.


Resumo Introdução: A rinossinusite crônica com pólipos nasais é uma doença heterogênea e algoritmos diagnósticos apropriados em casos individuais são necessários para um tratamento médico eficaz. Objetivo: O objetivo deste estudo foi esclarecer a relação entre a expressão da pendrina de pólipos nasais e propriedades clínicas e patológicas características da rinossinusite crônica eosinofílica. Método: Um total de 68 pacientes foram classificados como tendo rinossinusite crônica eosinofílica ou rinossinusite crônica não eosinofílica de acordo com o grau de infiltração eosinofílica nos pólipos nasais. Análises clínicas, hematológicas e imunohistoquímicas foram realizadas e comparadas estatisticamente entre os dois grupos. Resultados: Entre os pacientes, 38 apresentavam rinossinusite crônica eosinofílica e constituíram o grupo 1; 30 tinham rinossinusite crônica não eosinofílica e constituíram o grupo 2. Não houve diferenças significantes na distribuição etária, razão entre os sexos, prevalência de asma ou qualquer outra complicação entre os grupos. O escore médio de Lund-Mackay e o número de eosinófilos séricos foram significantemente maiores no grupo com rinossinusite crônica eosinofílica do que no grupo com rinossinusite crônica não eosinofílica. A expressão da pendrina foi mais frequentemente detectada na camada epitelial superficial dos pólipos nasais na rinossinusite crônica eosinofílica do que no grupo com rinossinusite crônica não eosinofílica. Além disso, mucina 5AC foi mais amplamente expressa na rinossinusite crônica eosinofílica do que na rinossinusite crônica não eosinofílica. Conclusão: O aumento da expressão da pendrina e mucina 5AC nos pólipos nasais estaria associado ao desenvolvimento de rinossinusite crônica eosinofílica. Esse achado pode permitir o desenvolvimento de um novo agente terapêutico voltado especificamente para pacientes com rinossinusite crônica eosinofílica.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Sinusite/metabolismo , Rinite/metabolismo , Pólipos Nasais/metabolismo , Eosinofilia/metabolismo , Transportadores de Sulfato/metabolismo , Asma/etiologia , RNA Mensageiro , Doença Crônica , Citocinas/metabolismo , Eosinofilia/etiologia
20.
Clin Sci (Lond) ; 133(22): 2301-2315, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31722010

RESUMO

Eosinophilic chronic rhinosinusitis with nasal polyps (ECRS) is a condition linked with type 2 inflammation, poor treatment outcomes, and high recurrence tendency. Although γδT cells have been reported to induce type 2 immune responses and eosinophilic infiltration in several diseases, their role in ECRS has not been fully explored. We aimed to evaluate the association of γδT cells with the type 2 inflammatory profiles in ECRS. Nasal tissue samples obtained from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (51 eosinophilic and 48 non-eosinophilic), 50 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 58 control subjects were examined for γδT cells, inflammatory markers and eosinophils using HE, RT-qPCR, ELISA, immunofluorescence, and flow cytometry. In parallel, studies were also conducted in an ECRS murine model induced by anti-γδT cells neutralizing antibody administration. γδT cells expression was significantly increased in tissues from patients with ECRS compared with non-ECRS, CRSsNP and control subjects. Moreover, inflammatory markers including type 2 proinflammatory cytokines (IL-4, IL-5, IL-13), GATA3, eosinophil cationic protein (ECP), and eotaxin levels were also increased in nasal tissues of patients with ECRS, and Vγ1+ γδT cells mRNA expression was positively correlated with type 2 cytokines, GATA3, and ECP. In the ECRS murine model, anti-Vγ1+ γδT antibody treatment reduced the infiltration of eosinophils and expression of type 2 cytokines, GATA3, and ECP in nasal mucosae. In conclusion, the results of the present study suggest that γδT cells play a crucial role in the type 2 inflammatory profiles and nasal tissue eosinophilic infiltration in patients with ECRS.


Assuntos
Eosinofilia/imunologia , Linfócitos Intraepiteliais/fisiologia , Pólipos Nasais/imunologia , Sinusite/imunologia , Animais , Biomarcadores/metabolismo , Doença Crônica , Citocinas/metabolismo , Eosinofilia/complicações , Eosinofilia/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Mucosa Nasal/metabolismo , Pólipos Nasais/complicações , Pólipos Nasais/metabolismo , Sinusite/complicações , Sinusite/metabolismo
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