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1.
Front Immunol ; 13: 1025796, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341332

RESUMO

Dysregulated innate and adaptive immune response to rhinoviral infection plays an important role in the exacerbation or progressive course of chronic rhinosinusitis (CRS). However, few studies have evaluated whether rhinovirus-induced production of anti-viral interferon is deficient or delayed in inflammatory epithelial cells of patients with CRS with nasal polyps. The aim of the present study is to investigate the replication rates of rhinovirus 16 (RV 16), RV16-induced antiviral interferon secretion, and the expression levels of pattern recognition receptors after RV 16 infection or TLR3 stimulation with poly (I: C) in normal and inflammatory epithelial cells. Inflammatory epithelial cells were obtained from CRS patients with nasal polyps and normal epithelial cells were derived from ethmoid sinus mucosa during endoscopic reduction of blowout fracture or uncinate process mucosa of patients with septal deviation. Cultured cells were infected with RV 16 or treated with poly (I: C) for 24, 48, and 72 h. Cells and media were harvested at each time point and used to evaluate RV16 replication rates, the secretion of IFN-ß, -λ1, -λ2, viperin, Mx, and OAS, and the expression levels of TRL3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3. RV replication rates reached peak levels 48 h after inoculation in both normal and inflammatory epithelial cells and showed no difference between both groups of epithelial cells at any time point. The release of IFN-ß, -λ1, and -λ2 in normal and inflammatory epithelial cells was also strongly induced 48 h after RV16 inoculation but reached peak levels 24 h after poly (I: C) treatment. The expression levels of viperin, Mx, OAS, TLR3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3 showed similar patterns in both groups of epithelial cells. These results suggest that the production of RV16-induced antiviral interferons is not deficient or delayed in inflammatory epithelial cells from CRS patients with nasal polyps.


Assuntos
Pólipos Nasais , Sinusite , Humanos , Rhinovirus , Pólipos Nasais/metabolismo , Receptor 3 Toll-Like/metabolismo , Antivirais/metabolismo , Sinusite/metabolismo , Células Epiteliais , Interferons/metabolismo , Interferon beta/metabolismo , Doença Crônica
2.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361742

RESUMO

Transglutaminase (TGM) isoform catalyze the cross-linking reaction of identical or different substrate proteins. Eosinophil has been recognized in chronic rhinosinusitis with nasal polyps (CRSwNP) forming tissue eosinophil in nasal polyp (NP), and TGM isoforms are suggested to be associated with a critical role in asthma and other allergic conditions. The aim of this study was to reveal the association of specific TGM isoform with both the tissue eosinophil infiltration deeply concerning with the intractable severity of CRSwNP and the fibrin polymerization ability of TGM isoform associated with the tissue eosinophil infiltration, which lead to NP formation and/or maintenance in CRSwNP. NP tissues (CRSwNP group) and uncinate process (UP) (control group) were collected from patients with CRSwNP and control subjects. We examined: (1) the expression level of TGM isoforms by using a real-time polymerase chain reaction (PCR) and the comparison to the issue eosinophil count in the CRSwNP group, (2) the location of specific TGM isoform in the mucosal tissue using immunohistochemistry, (3) the inflammatory cell showing the colocalization of specific TGM isoform in Laser Scanning Confocal Microscopy (LSCM) imaging, and (4) the fibrin polymerase activity of specific TGM isoform using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). A certain level of TGM 1, 2, 3, 5 expression was present in both the CRSwNP group and the control group. Only TGM 1 expression showed a positive significant correlation with the tissue eosinophil count in the CRSwNP group. The localization of TGM 1 in NP (CRSwNP) laid mainly in a submucosal layer as inflammatory cells and was at the cytoplasm in the tissue eosinophil. Fibrin polymerase activity of TGM 1 showed the same polymerase ability of factor XIIIA. TGM 1 might influence the NP formation and/or maintenance in CRSwNP related to the tissue eosinophil infiltration, which formed fibrin mesh composing NP stroma.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , Pólipos Nasais/patologia , Eosinófilos/metabolismo , Rinite/patologia , Fibrina/metabolismo , Polimerização , Sinusite/metabolismo , Transglutaminases/genética , Transglutaminases/metabolismo , Doença Crônica
3.
Mediators Inflamm ; 2022: 1061658, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211987

RESUMO

Background: Functional nasal endoscopic surgery (FESS) is an effective treatment approach for chronic rhinosinusitis with nasal polyps (CRSwNP) patients, but some patients still suffer from postoperative recurrence. This study is aimed at investigating the expression of multiple cytokines in CRSwNP and revealing their relationships with postoperative recurrence. Methods: A total of 72 patients with CRSwNP, including 36 primary and 36 recurrent patients, were enrolled. Serum samples were obtained, 30 cytokine levels were measured by multiplex analysis, and the association between cytokine levels and recurrence was assessed. The most potential cytokines were further validated in another independent cohort with 60 primary and 60 recurrent CRSwNP patients. Results: The results of multiple cytokine profiling exhibited that the levels of eotaxin, G-CSF, IFN-α, IL-13, IL-17A, IL-5, MCP-1, and RANTES were vastly changed in the recurrent group in comparison with the primary group. Receiver-operating characteristic (ROC) curves highlighted that serum levels of eotaxin, IL-17A, and RANTES were strongly predictive of postoperative recurrence (area under the curve (AUC) > 0.7, P < 0.05). Further validation results showed that elevated serum eotaxin, IL-17A, and RANTES levels were enhanced in the recurrent group. The ROC curve showed that serum eotaxin (AUC = 0.729, P < 0.001) and RANTES (AUC = 0.776, P < 0.001) exhibited stronger ability than serum IL-17A (AUC = 0.617, P = 0.027) in predicting CRSwNP recurrence. Conclusion: Our data suggested that serum multiple cytokine profiling was associated with postoperative recurrence of CRSwNP, and eotaxin and RANTES might serve as potential biomarkers for predicting postoperative recurrence. These results might contribute to the understanding of the underlying mechanisms of recurrence and provide novel clues for precision therapy in CRSwNP.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Biomarcadores/metabolismo , Quimiocina CCL5 , Doença Crônica , Citocinas/metabolismo , Fator Estimulador de Colônias de Granulócitos , Humanos , Interleucina-13 , Interleucina-17 , Interleucina-5 , Pólipos Nasais/metabolismo , Pólipos Nasais/cirurgia , Rinite/metabolismo , Rinite/cirurgia , Sinusite/metabolismo , Sinusite/cirurgia
4.
Int J Mol Sci ; 23(19)2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-36232588

RESUMO

The pathophysiology of chronic rhinosinusitis (CRS) is multifactorial and not entirely clear. The objective of the review was to examine the current state of knowledge concerning the role of exosomes in CRS. For this systematic review, we searched PubMed/MEDLINE, Scopus, CENTRAL, and Web of Science databases for studies published until 7 August 2022. Only original research articles describing studies published in English were included. Reviews, book chapters, case studies, conference papers, and opinions were excluded. The quality of the evidence was assessed with the modified Office and Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies. Of 250 records identified, 17 were eligible, all of which had a low to moderate risk of overall bias. Presented findings indicate that exosomal biomarkers, including proteins and microRNA, act as promising biomarkers in the diagnostics and prognosis of CRS patients and, in addition, may contribute to finding novel therapeutic targets. Exosomes reflecting tissue proteomes are excellent, highly available material for studying proteomic alterations noninvasively. The first steps have already been taken, but more advanced research on nasal exosomes is needed, which might open a wider door for individualized medicine in CRS.


Assuntos
Exossomos , MicroRNAs , Rinite , Sinusite , Animais , Biomarcadores/metabolismo , Doença Crônica , Exossomos/metabolismo , Humanos , MicroRNAs/metabolismo , Proteoma/metabolismo , Proteômica , Rinite/metabolismo , Sinusite/metabolismo
5.
Biomolecules ; 12(9)2022 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-36139155

RESUMO

Raftlin, as an inflammatory biomarker, has been previously reported in chronic inflammatory diseases. This study investigates the expression of Raftlin in cigarette smokers and in chronic rhinosinusitis with nasal polyps (CRSwNP), as well as evaluating its correlation with interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) levels. A total of 30 CRSwNP non-smoking and 16 CRSwNP + SK (smoking) patients undergoing endoscopic sinus surgery were enrolled, while 20 middle turbinate tissue pieces were examined and performed as the control group. In nasal mucosa epithelial staining, Raftlin levels were elevated in the columnar cells and were stained much more intensely in the CRSwNP and CRSwNP + SK groups. Raftlin was located more closely to the apical region of the epithelium in the CRSwNP + SK group; however, the Raftlin levels from whole nasal tissue pieces, according to ELISA data, showed that there was no significant difference between the three different study groups. A positive relationship by Pearson correlation was found between IL-17 or TNF-α levels and Raftlin levels. Taken together, these data indicate that increasing Raftlin expression in columnar cells might involve nasal epithelial remodeling in smokers with CRSwNP.


Assuntos
Proteínas de Membrana , Pólipos Nasais , Rinite , Sinusite , Biomarcadores , Doença Crônica , Humanos , Interleucina-17/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/metabolismo , Pólipos Nasais/metabolismo , Rinite/complicações , Rinite/metabolismo , Sinusite/metabolismo , Fumar/efeitos adversos , Fator de Necrose Tumoral alfa
6.
Clin Transl Med ; 12(8): e1021, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35988262

RESUMO

BACKGROUND: Eosinophilic inflammation is a hallmark of refractory chronic rhinosinusitis (CRS) and considered a major therapeutic target. Autophagy deficiency in myeloid cells plays a causal role in eosinophilic CRS (ECRS) via macrophage IL-1ß overproduction, thereby suggesting autophagy regulation as a potential therapeutic modality. Trehalose is a disaccharide sugar with known pro-autophagy activity and effective in alleviating diverse inflammatory diseases. We sought to investigate the therapeutic potential of autophagy-enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism focusing on macrophage IL-1ß production in ECRS pathogenesis. METHODS: We investigated the therapeutic effects of trehalose and saccharin on macrophage IL-1ß production and eosinophilia in the mouse model of ECRS with myeloid cell-specific autophagy-related gene 7 (Atg7) deletion. The mechanisms underlying their anti-inflammatory effects were assessed using specific inhibitor, genetic knockdown or knockout, and overexpression of cognate receptors. RESULTS: Unexpectedly, trehalose significantly attenuated eosinophilia and disease pathogenesis in ECRS mice caused by autophagy deficiency in myeloid cells. This autophagy-independent effect was associated with reduced macrophage IL-1ß expression. Various sugars recapitulated the anti-inflammatory effect of trehalose, and saccharin was particularly effective amongst other sugars. The mechanistic study revealed an involvement of sweet taste receptor (STR), especially T1R3, in alleviating macrophage IL-1ß production and eosinophilia in CRS, which was supported by genetic depletion of T1R3 or overexpression of T1R2/T1R3 in macrophages and treatment with the T1R3 antagonist gurmarin. CONCLUSION: Our results revealed a previously unappreciated anti-inflammatory effect of STR agonists, particularly trehalose and saccharin, and may provide an alternative strategy to autophagy modulation in the ECRS treatment.


Assuntos
Eosinofilia , Sinusite , Animais , Anti-Inflamatórios , Autofagia , Eosinofilia/complicações , Eosinofilia/tratamento farmacológico , Eosinofilia/metabolismo , Inflamação/complicações , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Camundongos , Sacarina/farmacologia , Sinusite/complicações , Sinusite/metabolismo , Paladar , Trealose/farmacologia
7.
Am J Rhinol Allergy ; 36(6): 816-826, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35915986

RESUMO

BACKGROUND: Hypersecretion of mucin 5AC (MUC5AC) is a prominent feature of chronic rhinosinusitis with nasal polyps (CRSwNP) and autophagy plays a pivotal role in this process. TNF receptor-associated factor 6 (TRAF6) functions as a signal transducer in many inflammation diseases, whereas the correlation between TRAF6 and autophagy in CRSwNP remains unclear. OBJECTIVE: To investigate the role of TRAF6 in the human neutrophil elastase (HNE)-induced autophagy and mucin MUC5AC over-expression in CRSwNP. METHODS: Tissue specimens were obtained from control subjects and patients with CRSwNP. The relationships between HNE, TRAF6, autophagy, and MUC5AC were investigated. The effect of TRAF6 on HNE-mediated autophagy and hypersecretion of MUC5AC was assessed by in-vitro culture of HNECs treated with human recombinant HNE. RESULTS: Patients with CRSwNP had more protein expression of HNE, MUC5AC, TRAF6, and light chain (LC3B), and increased levels of Beclin-1(BECN1) and autophagy-related gene 5 (ATG5) in mRNA level. Treatment of nasal epithelial cells with recombinant HNE induced the upregulation of TRAF6, autophagy, and MUC5AC. Alternatively, si-TRAF6 or autophagy inhibitor treatment mitigates the hyperexpression of MUC5AC before incubating with recombinant HNE. CONCLUSION: HNE promotes autophagy through TRAF6, resulting in hyperexpression of MUC5AC in CRSwNP.


Assuntos
Elastase de Leucócito , Pólipos Nasais , Rinite , Sinusite , Autofagia , Proteína Beclina-1/metabolismo , Doença Crônica , Humanos , Elastase de Leucócito/metabolismo , Mucina-5AC/genética , Mucina-5AC/metabolismo , Pólipos Nasais/metabolismo , RNA Mensageiro , Rinite/metabolismo , Sinusite/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-35917595

RESUMO

Severe nasal polyposis and mucosal inflammation, in patients with chronic rhinosinusitis (CRS) may include a dysregulated eicosanoid profile, but a clinical role for eicosanoids in CRS with nasal polyps (NP; CRSwNP) remains to be elucidated. This study focused on assessing levels and clinical implications of inflammatory mediators in nasal secretions and urine from patients with different NP severity or Aspirin Exacerbated Respiratory Disease (AERD). Levels of leukotrienes E4 and B4, prostaglandins D2 and E2 as well as 15(S)-hydroxyeicosatetraenoic acid were measured with enzyme immunoassays and cytokines with magnetic bead immunoassays. Patients with CRSwNP were subdivided based on NP score; CRSwNP-low (NP score ≤ 4, n = 11) or CRSwNP-high (NP score ≥ 5, n = 32) and compared to CRS without polyps (CRSsNP, n = 12), CRSwNP-AERD (n = 11) and individuals without CRS (n = 25). Smell test score, fractional exhaled nitric oxide (FeNO), blood eosinophils and Sinonasal outcome test-22 were assessed as clinical markers. Leukotriene E4, prostaglandin D2 and 15(S)-hydroxyeicosatetraenoic acid in nasal secretions correlated with NP score. Nasal leukotriene E4 also correlated with FeNO and smell test score, with highest levels found in CRSwNP-AERD. Levels of prostaglandin D2 in nasal secretion as well as urinary levels of the prostaglandin D2 metabolite 11ß-prostaglandin F2α differed between CRSNP-high and CRSwNP-low. Urinary 11ß-prostaglandin F2α was associated with asthma comorbidity whereas a similar association with prostaglandin D2 in nasal secretions was not observed. In conclusion, subdividing patients based on NP severity in combination with analysis of eicosanoids in non-invasively collected nasal secretions, may have clinical implications when assessing CRS disease severity.


Assuntos
Asma Induzida por Aspirina , Pólipos Nasais , Rinite , Sinusite , Asma Induzida por Aspirina/complicações , Asma Induzida por Aspirina/metabolismo , Doença Crônica , Eicosanoides/metabolismo , Humanos , Leucotrieno E4 , Pólipos Nasais/metabolismo , Prostaglandinas/metabolismo , Rinite/metabolismo , Sinusite/metabolismo
9.
Rhinology ; 60(4): 270-281, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35934314

RESUMO

BACKGROUND: The epithelial barrier plays an important role in the regulation of immune homeostasis. The effect of the immune environment on E-cadherin has been demonstrated in previous studies. This discovery prompted new research on the targeting mechanism of E-cadherin in chronic rhinosinusitis (CRS). METHODS: E-cadherin and p120 expression was determined by quantitative RT-PCR, and western blot. The interaction between E-cadherin and p120 was assessed by immunofluorescence staining and coimmunoprecipitation assays. Human nasal epithelial cells (HNECs) were cultured with submerged methods and transfected with p120-specific small interfering RNA. In other experiments, HNECs differentiated with the air-liquid interface (ALI) method were stimulated with various cytokines and Toll-like receptor (TLR) agonists. The barrier properties of differentiated HNECs were determined by assessing fluorescent dextran permeability. RESULTS: E-cadherin and p120 expression was decreased in HNECs from patients with CRS, and the p120 protein expression level was positively correlated with that of E-cadherin. Two isoforms of p120 (p120-1 and p120-3) were expressed in HNECs, with p120-3 being the main isoform. Knocking down p120 in HNECs cultured under submerged conditions significantly reduced the E-cadherin protein expression. The Rac1 inhibitor NSC23766 reversed the protein expression of E-cadherin in p120 knockdown experiments. Inflammatory mediators, including IL-4, TNF-α, TGF- ß, LPS and IFN-Î, reduced E-cadherin and p120 protein expression and increased paracellular permeability. Dexamethasone abolished the downregulation of E-cadherin and p120 caused by inflammatory mediators. CONCLUSIONS: p120 is involved in regulating E-cadherin protein expression in CRS. Dexamethasone may alleviate the reduction in E-cadherin and p120 protein expression caused by inflammatory mediators.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Cateninas/metabolismo , Sinusite , Células Cultivadas , Dexametasona/farmacologia , Células Epiteliais , Humanos , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/farmacologia , Sinusite/metabolismo
10.
BMC Immunol ; 23(1): 33, 2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35752781

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a group of heterogeneous diseases characterized by epithelial inflammation and tissue eosinophilic infiltration. IL-5, POSTN, and IL-33 are important factors that act as chemoattractants for eosinophils, and a tissue-remodeling protein positively correlated with eosinophils in blood and mediators of eosinophilic infiltration. The aim of the study was to determine the expression of IL-5, POSTN and IL-33, at the gene and protein levels, in eosinophilic CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP), and to correlate this expression with clinical severity. MATERIALS AND METHODS: The study included 40 CRSwNP patients and 53 CRSsNP patients and 40 control subjects. The expression of IL-5, POSTN and IL-33 mRNA was determined in sinonasal mucosal samples and in nasal polyp tissue by real-time PCR. Protein levels in the serum of CRSwNP patients were measured by ELISA. Computed tomography was evaluated according to Lund-Mackay scores, and visual analog scale scores were assessed. RESULTS: NP tissue demonstrated significantly higher IL-5 and POSTN mRNA expression than the sinonasal tissue in the CRSsNP and CRSwNP groups. CRS groups demonstrated elevated IL-33 mRNA expression in comparison to controls irrespective of the presence of NP. No correlation was found between IL-5, POSTN and IL-33 mRNA expression and disease severity. CRSwNP group demonstrated significantly higher serum IL-5, POSTN and IL-33 protein levels than controls, and this corresponds to disease severity. CONCLUSION: Serum IL-5, POSTN and IL-33 levels may be important markers for classification of eosinophilic CRSwNP patients, along with disease severity.


Assuntos
Eosinofilia , Interleucina-33/sangue , Interleucina-5/sangue , Pólipos Nasais , Rinite , Sinusite , Moléculas de Adesão Celular , Doença Crônica , Humanos , Interleucina-33/genética , Pólipos Nasais/genética , Pólipos Nasais/metabolismo , RNA Mensageiro/genética , Rinite/metabolismo , Sinusite/metabolismo
11.
Int J Mol Sci ; 23(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35682987

RESUMO

Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with inflammation and tissue remodeling including myofibroblasts differentiation and extracellular matrix (ECM) deposition mediated by TGF-ß1 and IL-4. Oncostatin M (OSM) is a cytokine involved in fibrotic processes in other cellular subtypes. We investigated the mechanisms of action of OSM in the fibrosis process associated with CRSwNP. The expression of IL-4, OSM and TGF-ß1 was assessed by RT-qPCR. Primary human cultures of nasal-polyp-derived fibroblasts were established and stimulated by TGF-ß1 and/or IL-4 and/or OSM. The expression of ECM components and αSMA was determined by RT-qPCR and Western blot. TGF-ß1-Smad3 signaling was investigated by immunofluorescence. TGF-ß1, IL-4 and OSM as well as αSMA were overexpressed in nasal polyps when compared to noninflammatory nasal mucosa. In TGF-ß1-stimulated nasal-polyp-derived fibroblasts, ECM genes and αSMA gene and protein were overexpressed, as well as αSMA in IL-4-stimulated fibroblasts. OSM counteracted the profibrotic effect of TGF-ß1 on ECM components and αSMA. TGF-ß1-induced nuclear translocation of Smad3 was completely reversed by OSM. OSM counteracts the profibrotic effect of IL-4 and also TGF-ß1, by inhibiting the nuclear translocation of Smad3. We suggest OSM could be an efficient tool to protect against fibrosis in CRSwNP.


Assuntos
Pólipos Nasais , Sinusite , Células Cultivadas , Fibroblastos/metabolismo , Fibrose , Humanos , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Pólipos Nasais/genética , Oncostatina M/metabolismo , Oncostatina M/farmacologia , Sinusite/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Int Arch Allergy Immunol ; 183(9): 1017-1028, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35660678

RESUMO

BACKGROUND: Glucocorticoid (GC) resistance results in unsatisfactory outcomes in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. Previous studies have shown that calcitriol, the active form of vitamin D, alone or in combination with corticosteroids, exerts crucial immunomodulatory effects on inflammatory responses. However, whether vitamin D can improve the effect of GCs to attenuate inflammation in the epithelium of CRSwNP remains unclear. METHODS: A human bronchial epithelial cell line (Beas-2B) and primary human nasal epithelial cells (HNECs) obtained from 10 patients with CRSwNP were exposed to lipopolysaccharide (LPS) for 24 h to establish an inflammation model. LPS-stimulated HNECs and Beas-2B cells were treated with/without dexamethasone in the presence or absence of calcitriol pretreatment for 24 h. The expression levels of interleukin-6 (IL-6) mRNA and protein were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Toll-like receptor 4 (TLR4)/NF-κB pathway related markers were examined by western blotting. One-way ANOVA or the Kruskal-Wallis test with post hoc analysis were used for multiple comparisons among groups. RESULTS: The production of IL-6 in Beas-2B cells and primary HNECs after LPS stimulation was significantly increased, which could be inhibited by dexamethasone or calcitriol alone. However, significant inhibition of IL-6 production was observed in the calcitriol plus dexamethasone group. Further analysis showed that calcitriol could enhance the effect of dexamethasone in inhibiting LPS-induced overexpression of TLR4, Myd88, and phosphorylation of p65. CONCLUSION: Our findings demonstrated that vitamin D could improve the effect of GCs to alleviate the level of IL-6 induced by LPS via the TLR4/NF-κB pathway in human respiratory epithelial cells.


Assuntos
Pólipos Nasais , Sinusite , Calcitriol/farmacologia , Dexametasona/farmacologia , Células Epiteliais/metabolismo , Glucocorticoides , Humanos , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Pólipos Nasais/metabolismo , Transdução de Sinais , Sinusite/metabolismo , Receptor 4 Toll-Like/genética , Vitamina D
13.
Int Arch Allergy Immunol ; 183(10): 1029-1039, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35738243

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a common condition in otorhinolaryngology. It is characterized by chronic inflammation of the nasal cavity and the sinus mucosa. However, its specific pathogenesis remains unclear. Epithelial dysfunction is closely related to inflammatory airway diseases. Various evidences support that epithelial-mesenchymal transition (EMT) plays a key role in the development of CRS. OBJECTIVE: The study aimed to explore our understanding of how EMT contributes to the pathogenesis of CRS and to examine the role of several signaling pathways in EMT. METHODS: PubMed database was used to review the literature related to EMT in CRS pathogenesis. The following key words were used for the search strategy: CRS, sinusitis, nasal polyps, epithelial cells, EMT, dysfunction, cytokines, signaling pathways, pathogenesis, and therapy. RESULTS: EMT is widely present in the nasal mucosa of CRSwNP patients and contributes to the pathogenesis of the disease. However, there is no sufficient evidence for the existence of EMT in CRSsNP. Multiple signaling pathways and molecules, such as transforming growth factor-ß signaling, Wnt signaling, and hypoxia-inducible factor-1α signaling, have been found to be involved in the EMT process and promote CRSwNP. CONCLUSION: EMT is closely associated with CRS pathogenesis. Our study supports further research on epithelial EMT changes in CRS patients and provides a basis for revealing its pathogenesis and exploring new treatments.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Citocinas , Transição Epitelial-Mesenquimal , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Fatores de Crescimento Transformadores , Via de Sinalização Wnt
14.
J Allergy Clin Immunol ; 150(5): 1114-1124.e3, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35728655

RESUMO

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.


Assuntos
Asma Induzida por Aspirina , Pólipos Nasais , Rinite , Sinusite , Humanos , Pólipos Nasais/metabolismo , Rinite/metabolismo , Ativador de Plasminogênio Tecidual , Interleucina-13 , Fibrinólise , Tretinoína/farmacologia , Células Endoteliais/metabolismo , Sinusite/metabolismo , Asma Induzida por Aspirina/complicações , Doença Crônica , Fibrina
15.
Artigo em Chinês | MEDLINE | ID: mdl-35725311

RESUMO

Objective: To preliminarily analyze the expression of angiotensin-converting enzyme 2 (ACE2) and to investigate its potential regulatory mechanism in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: Patients underwent nasal endoscopic surgery in the Third Affiliated Hospital of Sun Yat-sen University from February 2020 to May 2021 were selected, including 17 males and 6 females, aging from 23 to 66 years old. Expression of ACE2 was evaluated via immunohistochemical staining in controls with non-chronic rhinosinusitis, non-eosinophilic CRSwNP (non-ECRSwNP), and eosinophilic CRSwNP (ECRSwNP) tissue, respectively. Correlations between ACE2 and the indicated Th1/Th2-related cytokines (IFN-γ, IL-4, IL-5, IL-13, IL-25, IL-33, TSLP and periostin) were analyzed based on GSE72713 dataset. Protein-protein interaction (PPI) network was constructed via string database, immune infiltration of GSE72713 dataset was evaluated using cibersort algorithm. ACE2 was comprehensively analyzed by microRNA regulatory network, gene set enrichment analysis (GSEA) and pharmacological analysis. Statistical analysis was performed using GraphPad 7.0 and SPSS 20.0 software. Results: ACE2 was up-regulated in non-ECRSwNP compared with ECRSwNP. Microarray analysis showed that ACE2 was positively correlated with IFN-γ while inversely correlated with IL-5, IL-13 and periostin significantly. Analysis of immune infiltration suggested that ACE2 expression correlated positively with the number of M1 macrophage while negatively with M2 macrophage. GSEA demonstrated that interferon-related signaling pathways were up-regulated in non-ECRSwNP, and miRNA-200B/miRNA-200C/miRNA-429 pathways targeting ACE2 were enriched in ECRSwNP. Results of pharmacological analysis indicated that ampicillin was able to promote the expression of ACE2 whereas acetaminophen could down regulated the expression of ACE2. Conclusion: Expression pattern of ACE2 is varied in non-ECRSwNP and ECRSwNP, which may be related to the different infiltration of indicated cytokines and different regulatory pathways of miRNA.


Assuntos
Enzima de Conversão de Angiotensina 2 , MicroRNAs , Pólipos Nasais , Rinite , Sinusite , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/genética , Doença Crônica , Citocinas , Eosinófilos/metabolismo , Feminino , Humanos , Interleucina-13 , Interleucina-5 , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Pólipos Nasais/metabolismo , Rinite/complicações , Rinite/metabolismo , Sinusite/complicações , Sinusite/metabolismo , Adulto Jovem
16.
Int Forum Allergy Rhinol ; 12(12): 1535-1550, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35514144

RESUMO

BACKGROUND: The role of periostin, a matricellular protein encoded by the POSTN gene, in chronic rhinosinusitis with nasal polyposis (CRSwNP) is reviewed. Periostin is considered a potential biomarker of endotype and may be useful for evaluating response to treatment. METHODS: Search terms in PubMed and Web of Science (1990-March 2022) included: ((periostin) OR (POSTN)) AND ((sinusitis) OR (nasal polyp) OR (CRSwNP) OR (CRS). The primary outcomes were differences in tissue, serum, and nasal lavage between CRSwNP and CRS without NP (CRSsNP) or controls. Associated factors reported to affect periostin expression, data regarding participants' clinical characteristics, disease endotypes, laboratory methods, and samples' origin were also pooled. Studies on <10 patients were excluded. RESULTS: Out of 101 records harvested through database searching, 29 prospective cross-sectional or case-control studies were eligible for review and qualitative analysis. Tissue sample origin, concurrent infection, current and past medication, primary or recurrent disease, allergic rhinitis, and smoking status should be considered as confounding factors for periostin levels. Periostin and POSTN messenger RNA (mRNA) levels were consistently and significantly higher in CRSwNP than CRSsNP and controls. Despite the distinctly different inflammation patterns among CRSwNP endotypes, periostin-related remodeling patterns seemed to be similar. CONCLUSION: Tissue and serum periostin levels, and POSTN expression appear elevated in CRSwNP, especially in eosinophilic inflammation, compared to CRSsNP and controls. Disease severity and comorbidities are also reflected in periostin and POSTN values. Carefully designed prospective studies may establish the role of periostin as a biomarker in CRSwNP and allow its incorporation in clinical practice.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , Biomarcadores , Doença Crônica , Estudos Transversais , Inflamação , Pólipos Nasais/metabolismo , Estudos Prospectivos , Sinusite/metabolismo
17.
Allergy ; 77(11): 3217-3232, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35603933

RESUMO

Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nasal cavity characterized by excessive nasal mucus secretion and nasal congestion. The development of CRS is related to pathological mechanisms induced by hypoxia. Under hypoxic conditions, the stable expression of both Hypoxia inducible factor-1 (HIF-1) α and HIF-2α are involved in the immune response and inflammatory pathways of CRS. The imbalance in the composition of nasal microbiota may affect the hypoxic state of CRS and perpetuate existing inflammation. Hypoxia affects the differentiation of nasal epithelial cells such as ciliated cells and goblet cells, induces fibroblast proliferation, and leads to epithelial-mesenchymal transition (EMT) and tissue remodeling. Hypoxia also affects the proliferation and differentiation of macrophages, eosinophils, basophils, and mast cells in sinonasal mucosa, and thus influences the inflammatory state of CRS by regulating T cells and B cells. Given the multifactorial nature in which HIF is linked to CRS, this study aims to elucidate the effect of hypoxia on the pathogenic mechanisms of CRS.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , Pólipos Nasais/metabolismo , Sinusite/etiologia , Sinusite/metabolismo , Eosinófilos/metabolismo , Transição Epitelial-Mesenquimal , Doença Crônica , Hipóxia/metabolismo , Rinite/etiologia , Rinite/metabolismo , Mucosa Nasal/metabolismo
18.
Eur J Immunol ; 52(8): 1308-1320, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35524548

RESUMO

Human nasal mucosa is susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and serves as a reservoir for viral replication before spreading to other organs (e.g. the lung and brain) and transmission to other individuals. Chronic rhinosinusitis (CRS) is a common respiratory tract disease and there is evidence suggesting that susceptibility to SARS-CoV-2 infection differs between the two known subtypes, eosinophilic CRS and non-ECRS (NECRS). However, the mechanism of SARS-CoV-2 infection in the human nasal mucosa and its association with CRS has not been experimentally validated. In this study, we investigated whether the human nasal mucosa is susceptible to SARS-CoV-2 infection and how different endotypes of CRS impact on viral infection and progression. Primary human nasal mucosa tissue culture revealed highly efficient SARS-CoV-2 viral infection and production, with particularly high susceptibility in the NECRS group. The gene expression differences suggested that human nasal mucosa is highly susceptible to SARS-CoV-2 infection, presumably due to an increase in ACE2-expressing cells and a deficiency in antiviral immune response, especially for NECRS. Importantly, patients with NECRS may be at a particularly high risk of viral infection and transmission, and therefore, close monitoring should be considered.


Assuntos
COVID-19 , Rinite , Sinusite , Doença Crônica , Humanos , Mucosa Nasal/metabolismo , Rinite/complicações , Rinite/metabolismo , SARS-CoV-2 , Sinusite/complicações , Sinusite/metabolismo
19.
J Allergy Clin Immunol ; 150(3): 727-735.e6, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35460727

RESUMO

BACKGROUND: Although metabolomics provides novel insights into disease mechanisms and biomarkers, the metabolic alterations in local tissues affected by chronic rhinosinusitis (CRS) are unknown. OBJECTIVE: This study aimed to determine the metabolomic profiles of sinonasal tissues associated with different types of CRS and their treatment outcomes. METHODS: Untargeted metabolomic profiling was performed on sinonasal tissues obtained from patients with eosinophilic CRS with nasal polyps (CRSwNP), noneosinophilic CRSwNP or CRS without nasal polyps (CRSsNP), and controls. The messenger RNA (mRNA) levels of inflammatory cytokines in nasal tissues were detected by quantitative real-time reverse transcriptase PCR. Nasal polyp tissues were cultured ex vivo and treated with glutathione. RESULTS: Distinct metabolomic profiles were observed for the CRS subtypes. Eosinophilic CRSwNP had profoundly enhanced unsaturated fatty acid oxidization, which correlated with mucosal eosinophil numbers and IL-5 mRNA levels. Noneosinophilic CRSwNP was characterized by uric acid accumulation. Increased uric acid levels were positively correlated with mucosal neutrophil numbers and IFN-γ, IL-17A, IL-1ß, and IL-8 mRNA levels. Disrupted purine metabolism was specifically detected in CRSsNP. Reduced levels of amino acid metabolites were found in eosinophilic CRSwNP and CRSsNP, and were inversely associated with mucosal total inflammatory cell numbers and inflammatory cytokines. Compared to non-difficult-to-treat CRS, difficult-to-treat CRS had higher glutathione disulfide levels, which were positively correlated with IL-8 mRNA levels. Glutathione treatment reduced IL-8 mRNA expression in cultured nasal polyp tissues. CONCLUSIONS: Specific metabolic signatures are associated with different types of CRS, inflammatory patterns, and disease outcomes, which may provide novel insights into pathophysiologic mechanisms, subtype-specific biomarkers, and treatment targets of CRS.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Biomarcadores , Doença Crônica , Citocinas/metabolismo , Glutationa , Humanos , Interleucina-8 , Pólipos Nasais/metabolismo , RNA Mensageiro , Rinite/metabolismo , Sinusite/metabolismo , Ácido Úrico
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