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1.
Inflamm Res ; 73(4): 499-513, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38393344

RESUMO

BACKGROUD: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP). METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay. RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks. CONCLUSIONS: Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , NF-kappa B/metabolismo , Eosinófilos , Regulação para Cima , Sistema de Sinalização das MAP Quinases , Interleucinas/genética , Interleucinas/metabolismo , Epitélio , Doença Crônica
2.
J Allergy Clin Immunol ; 152(3): 641-655.e14, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37164271

RESUMO

BACKGROUND: Regulatory T (Treg) cells, which prevent inflammation-induced eosinophil infiltration, are deficient in nasal polyps (NPs) in patients with eosinophilic chronic rhinosinusitis (ECRS). It is concomitant with loss of Foxp3 after certain inflammatory stimuli. OBJECTIVE: We sought to determine the inflammatory cytokines involved in inducing the loss of Treg cells in NPs. METHODS: The abundance of cytokines in ECRS patients or mice were tested using ELISA, immunochemistry, immunofluorescence, quantitative reverse transcription PCR (qPCR), and/or flow cytometry. Expression of eosinophil cationic protein (ECP), CD4+ T cells, IL-4, and IL-17A and eosinophils in nasal mucosa of mouse model was investigated by immunochemistry, immunofluorescence, and hematoxylin and eosin staining. The percentage and death of induced Treg (iTreg) cells, source of IL-21 in NPs from ECRS and non-ECRS patients, and abundance of different systemic phenotypes of CD4+ T cells in a mouse model were studied by flow cytometry. Western blot analysis, scanning, and transmission electronic microscopy were used to detect pyroptosis of iTreg cells. RESULTS: IL-21 was highly expressed in nasal mucosa of ECRS patients and mice, causing pyroptosis and preventing development of iTreg cells in vitro. The elevated IL-21 in NPs from ECRS patients was mainly produced by CD3+ T cells, including T follicular helper, T peripheral helper, TH2, and TH17 cells and CD3+CD4- T cells. T peripheral helper cells and CD3+CD4- T cells were the predominant source of IL-21 in NPs from non-ECRS patients. Blocking IL-21/IL-21R signaling significantly reduced the number of eosinophils and CD4+ T cells along with ECP, IL-4, and IL-17A expression in the nasal mucosa of ECRS mice. It also increased Treg cell percentage and systemically decreased TH2 and TH17 ratios. Akt-mTOR inhibition prevented IL-21-induced pyroptosis in human and mouse iTreg cells. CONCLUSION: Elevated IL-21 drives pyroptosis and prevents Treg cell development in ECRS patients. IL-21 induced pyroptosis via activating Akt-mTOR-NLRP3-caspase 1 signaling.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , Animais , Camundongos , Linfócitos T Reguladores/metabolismo , Caspase 1 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas Proto-Oncogênicas c-akt , Interleucina-17 , Rinite/metabolismo , Piroptose , Interleucina-4 , Sinusite/metabolismo , Citocinas/metabolismo , Doença Crônica , Eosinófilos/patologia , Serina-Treonina Quinases TOR , Pólipos Nasais/metabolismo
3.
Inflamm Res ; 72(1): 43-55, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36316415

RESUMO

BACKGROUND: Tissue remodeling is a prominent characteristic of chronic rhinosinusitis (CRS). Excess deposition of fibronectin (FN) and collagen (Col) I by fibroblasts is crucial for the pathologic tissue remodeling in CRS without nasal polyps (CRSsNP). Increased interleukin (IL)-19 level in patients with CRS had been demonstrated in our previous studies. Here, we aimed to evaluate the role of IL-19 in mediating FN and Col I expression in CRS. METHODS: Nasal mucosal tissue samples were collected from patients with CRS with nasal polyps (CRSwNP), CRSsNP, and controls. The expression of IL-19, vimentin, FN, and Col I were detected using immunohistochemistry and immunofluorescence. Primary human nasal fibroblasts were treated with IL-19, then the activation of Smad2/3, NF-κB and relevant pathways, and the expression of FN and Col I were measured. RESULTS: Expression levels of vimentin, FN, and Col I were significantly increased in nasal tissues from patients with CRSsNP compared with CRSwNP and control subjects. Moreover, IL-19 co-localized with FN and Col Ι in nasal tissues. IL-19-treated fibroblasts had increased production of FN and Col I, which was associated with the activated Smad2/3 and NF-κB pathways. Moreover, Smad2/3 activation was mediated by the NF-κB pathway in IL-19-treated fibroblasts. CONCLUSIONS: IL-19 promotes FN and Col I production via the activated NF-κB-Smad2/3 pathway in fibroblasts, leading to fibrosis and collagen deposition in patients with CRS.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Humanos , NF-kappa B/metabolismo , Fibronectinas/metabolismo , Vimentina , Interleucinas/metabolismo , Doença Crônica , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Proteína Smad2
4.
J Allergy Clin Immunol ; 150(2): 337-351, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35346673

RESUMO

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.


Assuntos
Interleucina-17 , Pólipos Nasais , Piroptose , Sinusite , Caspases/metabolismo , Doença Crônica , Humanos , Interleucina-17/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasais/patologia , Receptores de Glucocorticoides/metabolismo , Sinusite/patologia , Esteroides
5.
Clin Sci (Lond) ; 134(2): 123-138, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31922185

RESUMO

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-ß and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.


Assuntos
Eosinófilos/imunologia , Inflamação/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Sinusite/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Animais , Povo Asiático , Antígenos CD4/metabolismo , Doença Crônica , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Interleucina-10/biossíntese , Masculino , Camundongos Endogâmicos BALB C , Pólipos Nasais/sangue , Pólipos Nasais/complicações , Pólipos Nasais/genética , Pólipos Nasais/imunologia , Rinite/sangue , Rinite/complicações , Rinite/genética , Rinite/imunologia , Sinusite/sangue , Sinusite/complicações , Sinusite/genética , Células Th17/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/biossíntese
6.
ORL J Otorhinolaryngol Relat Spec ; 82(5): 257-267, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726776

RESUMO

OBJECTIVE: To investigate the expression of interleukin-17A (IL-17A) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and to analyze its effect on prognosis and to explore the role and mechanism of anti-IL-17A effect in vivo by establishing a murine nasal polyps (NP) model. METHODS: Patients with CRSwNP who underwent endoscopic sinus surgery and matched control subjects were collected. We investigated IL-17A expression in human NP tissues using immunohistochemistry and analyzed their clinical features, including Lund-Mackay computed tomography scoring (LMCS) before surgery, Lund-Kennedy endoscopic scoring (LKES) before surgery (LKES B), LKES 6 months after surgery (LKES A), and reduction of LKES (LKES R). Then, after establishing the murine NP model to detect the expression and correlation of IL-17A and matrix metalloproteinase-9 (MMP-9) in nasal tissue, we studied nasal lavage fluid and serum by PCR and enzyme-linked immunosorbent assay in vivo. Anti-IL-17A treatment was administered in the murine NP model to confirm the function of IL-17A during the pathogenic processes. RESULTS: IL-17A expression was upregulated in NP tissues from patients with CRSwNP compared with control subjects (p < 0.001). The number of IL-17A+ cells was significantly negatively correlated with LKES R in patients with CRSwNP (p < 0.01). However, there was no significant correlation between IL-17A and LMCS or LKES B (all p < 0.05). Further, IL-17A and MMP-9 were more abundant in nasal mucosa of the murine NP model compared with that of control mice (all p < 0.05), and severe polypoid lesions were apparently observed in murine NP models. Anti-IL-17A treatment downregulated the mRNA and protein expression of MMP-9 in nasal mucosa and reduced the number of polypoid lesions in the murine NP model (all p < 0.05). CONCLUSION: Our results suggest that IL-17A plays a crucial role and may affect the prognosis of CRSwNP. Anti-IL-17A treatment may reduce the formation of polypoid lesions through inhibition of MMP-9 expression.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Animais , Doença Crônica , Humanos , Interleucina-17 , Camundongos , Pólipos Nasais/complicações , Prognóstico , Rinite/complicações , Sinusite/complicações
7.
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
8.
Eur Arch Otorhinolaryngol ; 276(5): 1397-1403, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788581

RESUMO

PURPOSE: Budesonide improves the prognosis of chronic rhinosinusitis (CRS). However, few reports have examined whether its use for nasal irrigation, compared to normal saline, improves the prognosis of patients after endoscopic sinus surgery (ESS). We compared the effects of nasal irrigation with budesonide and normal saline in CRS patients after ESS. METHODS: Sixty CRS patients who had undergone ESS were randomly divided into an experimental group (30 patients), which used budesonide nasal irrigation, and a control group (30 patients), which used normal saline nasal irrigation. All patients received regular follow-up evaluations and were assessed via questionnaires, including the Lund-Kennedy endoscopic score (LKES), the symptom visual analog scale (VAS), the 22-item Sino-Nasal Outcome Test (SNOT-22), the Short-Form 36-Item Questionnaire (SF-36), the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS) and a side effects scale. RESULTS: Scores of polyposis, mucosal edema, secretions and total score of LKES; VAS scores of nasal blockage, hyposmia and rhinorrhea; and SNOT-22 results in both groups were significantly improved 3 months after ESS. Scores of polyposis, mucosal edema, secretions and scarring and total score of LKES in experimental group were significantly better than in control group 3 months after ESS. No significant differences were observed in SF-36, SAS or SDS before or 3 months after ESS within or between the two groups. The side effects of the two groups were not significantly different. CONCLUSIONS: Nasal irrigation improved the prognosis of CRS patients after ESS. Budesonide nasal irrigation had a better effect than normal saline nasal irrigation.


Assuntos
Budesonida/administração & dosagem , Endoscopia , Lavagem Nasal/métodos , Obstrução Nasal , Seios Paranasais , Rinite , Sinusite , Adulto , Anti-Inflamatórios/administração & dosagem , Doença Crônica , Endoscopia/efeitos adversos , Endoscopia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obstrução Nasal/diagnóstico , Obstrução Nasal/etiologia , Obstrução Nasal/prevenção & controle , Seios Paranasais/diagnóstico por imagem , Seios Paranasais/efeitos dos fármacos , Seios Paranasais/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Prognóstico , Rinite/diagnóstico , Rinite/cirurgia , Sinusite/diagnóstico , Sinusite/cirurgia , Resultado do Tratamento
9.
ORL J Otorhinolaryngol Relat Spec ; 79(5): 251-263, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28858878

RESUMO

BACKGROUND/AIMS: To examine whether γδ T cell is expressed in the nasal mucosa of chronic rhinosinusitis (CRS) patients and its potential association with recurrence of nasal polyps. METHODS: Thirty-six patients with CRS with nasal polyps (CRSwNP) and 25 patients with CRS without nasal polyps (CRSsNP) were recruited. Twenty-six patients with other nasal diseases served as controls. The CRSwNP group was divided into the eosinophilic CRSwNP and noneosinophilic CRSwNP groups. The expression of γδ T cells was detected by immunohistochemistry. The expression of each subtype of γδ T cells was detected by using qRT-PCR. All patients underwent nasal endoscopy, and postoperative follow-up lasted over 12 months. CRS patients were evaluated by preoperative VAS scores of symptoms and nasal endoscopy Lund-Kennedy scores. RESULTS: The expression of γδ T cells in the CRSwNP groups was stronger than in the CRSsNP and the control group (p < 0.05, p < 0.05). The expression of Vγ1+γδ T cells in the eosinophilic CRSwNP group was higher than that in the CRSsNP group and the control group (p < 0.05, p < 0.05). The expression of γδ T cells was associated with high rate of recurrence, tissue eosinophil infiltration, worse symptom score of nasal obstruction, and higher Lund-Kennedy score (all p < 0.05). CONCLUSIONS: Increased expression of γδ T cells in CRSwNP may be associated with recurrence of nasal polyps.


Assuntos
Linfócitos Intraepiteliais/patologia , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia , Adolescente , Adulto , Idoso , Doença Crônica , Endoscopia , Eosinofilia/complicações , Eosinófilos , Feminino , Humanos , Imuno-Histoquímica , Linfócitos Intraepiteliais/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Pólipos Nasais/complicações , Pólipos Nasais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Estudos Retrospectivos , Rinite/complicações , Rinite/metabolismo , Sinusite/complicações , Sinusite/metabolismo , Escala Visual Analógica , Adulto Jovem
11.
BMC Cancer ; 16: 190, 2016 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-26951044

RESUMO

BACKGROUND: The Mre11-Rad50-Nbs1 (MRN) complex is well known for its crucial role in initiating DNA double strand breaks (DSBs) repair pathways to resistant irradiation (IR) injury and thus facilitating radioresistance which severely reduces radiocurability of nasopharyngeal cancer (NPC). Targeting native cellular MRN function would sensitize NPC cells to IR. METHODS: A recombinant adenovirus containing a mutant Rad50 gene (Ad-RAD50) expressing Rad50 zinc hook domain but lacking the ATPase domain and the Mre11 interaction domain was constructed to disrupt native cellular MRN functions. The effects of Ad-RAD50 on the MRN functions were assessed in NPC cells lines using western blot, co-immunoprecipitation and confocal microscopy analyses. The increased radiosensitivity of transient Ad-RAD50 to IR was examined in NPC cells, including MTT assay, colony formation. The molecular mechanisms of radiosensitization were confirmed by neutral comet assay and western bolts. Nude mice subcutaneous injection, tumor growth curve and TUNEL assay were used to evaluate tumor regression and apoptosis in vivo. RESULTS: Rad50 is remarkably upregulated in NPC cells after IR, implying the critical role of Rad50 in MRN functions. The transient expression of this mutant Rad50 decreased the levels of native cellular Rad50, Mre11 and Nbs1, weakened the interactions among these proteins, abrogated the G2/M arrest induced by DSBs and reduced the DNA repair ability in NPC cells. A combination of IR and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage, prevented proliferation and cell viability. Furthermore, Ad-RAD50 sensitized NPC cells to IR by causing dramatic tumor regression and inducing apoptosis in vivo. CONCLUSION: Our findings define a novel therapeutic approach to NPC radiosensitization via targeted native cellular Rad50 disruption.


Assuntos
Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias Nasofaríngeas/genética , Tolerância a Radiação/genética , Hidrolases Anidrido Ácido , Animais , Apoptose , Carcinoma , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Proteína Homóloga a MRE11 , Camundongos , Complexos Multiproteicos , Mutação , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/radioterapia , Proteínas Nucleares/metabolismo , Ligação Proteica , Radiação Ionizante , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Pediatr Res ; 78(2): 165-73, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25860501

RESUMO

BACKGROUND: To characterize the distribution of both tonsillar and circulating CD4(+)T-lymphocyte subsets, and to explore their clinical relevance in nonobese children with obstructive sleep apnea syndrome (OSAS). METHODS: A total of 53 children who underwent tonsillectomy for either OSAS (n = 25) or primary snoring (PS, n = 28) were prospectively enrolled. Nineteen healthy children without any symptoms were recruited as controls. We quantified the frequencies of CD4(+)T-lymphocyte subpopulations using flow cytometry, serum-related cytokines using enzyme-linked immunosorbent assay, and key transcription factors using quantitative polymerase chain reaction (qPCR). RESULTS: Tonsillar distributions of CD4(+)T-lymphocyte subsets were comparable in the OSAS and PS subjects. The peripheral Th17/Treg ratio was positively correlated to severity as measured by apnea/hypopnea index (AHI), serum C-reactive protein and hypoxia-inducible factor-1α mRNA in the OSAS children (P < 0.05). And AHI was independently associated with the peripheral Th17/Treg ratio (P < 0.05). Furthermore, the response to surgery was associated with a significant reversal of the Th17/Treg imbalance and a concomitant relief of the proinflammatory profile in the OSAS subjects. CONCLUSION: Pediatric OSAS was associated with an altered Th17:Treg balance toward Th17 predominance. The changes in lymphocytic phenotypes that correlated with recurrent intermittent hypoxia in sleep apnea may contribute to the variance in systemic inflammation and downstream morbidities of pediatric OSAS.


Assuntos
Linfócitos T CD4-Positivos/citologia , Apneia Obstrutiva do Sono/sangue , Subpopulações de Linfócitos T , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Apneia Obstrutiva do Sono/cirurgia , Tonsilectomia
13.
Eur Arch Otorhinolaryngol ; 272(3): 591-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24906844

RESUMO

This study aimed to improve the surgical removal procedure for nasal vestibular cysts. Twenty-three patients with nasal vestibular cysts underwent surgical removal of the cyst via a transoral sublabial approach and another 30 patients via a modified intranasal endoscopic excision method. The 30 patients were treated with local anesthesia and the roof of the cyst, which was firmly attached to the mucous membrane of the anterior floor of the nasal cavity, was removed transnasally with microdebrider. Bleeding of the opening was stopped by electric coagulation without nasal packing. Among the 30 consecutive patients who underwent the modified surgical procedure, all patients were successfully treated. The mean duration of surgery was 5.7 ± 2.6 min. The mean estimated blood loss was 3.5 ± 2.1 ml. All patients were outpatients. The mean hospital stay was 1 h. The mean total cost was 140. The visual analog scale scores of postoperative pain, pressure and nasal obstruction were 1, 0 and 1, respectively. The incidence rate of postoperative lip swelling or numbness was 0 %. Postoperative endoscopic findings revealed that the cyst was replaced by an air-containing sinus with a persistent opening at the anterolateral nasal floor. There was no recurrence during a mean follow-up of 18 months. The modified intranasal endoscopic excision is a simple, less invasive, low-cost and effective surgical procedure for the treatment of nasal vestibular cysts. It might change the pattern of treatment for nasal vestibular cysts in China.


Assuntos
Cistos/cirurgia , Endoscopia/métodos , Cavidade Nasal/cirurgia , Doenças Nasais/cirurgia , Adolescente , Adulto , Procedimentos Cirúrgicos Ambulatórios , Perda Sanguínea Cirúrgica , China , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Escala Visual Analógica , Adulto Jovem
14.
J Transl Med ; 12: 24, 2014 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-24460842

RESUMO

BACKGROUND: T regulatory cell (Treg) plays a critical role in respiratory allergy and allergen-specific immunotherapy (SIT), and γδ T cells might participate in mediating Treg quantity and/or function in some immunological diseases. To further characterize whether γδ T cells could influence Treg in allergic rhinitis (AR) and SIT, we investigated the expression pattern of Treg's Foxp3 gene and γδ T cell receptor (TCR) Vγ subfamily genes in peripheral blood mononuclear cells (PBMCs) of AR patients before and after SIT. METHODS: Eighteen AR patients undergoing effective SIT with house dust mite extract for one year were recruited. Visual Analogue Scale (VAS) was applied to evaluate the severity. Immunofluorescence quantification analysis was performed to determine the serum specific IgE (sIgE) content. Real-time PCR was used to detect the expression levels of Foxp3 and TCR Vγ subfamilies. Ten healthy volunteers were recruited as the controls. RESULTS: Nasal uni-VAS score after SIT was significantly lower than that before SIT, while serum sIgE content was similar before and after SIT. Expression levels of Foxp3 and TCR Vγ subfamilies in AR patients before treatment were significantly lower than those in healthy subjects. Expression levels of VγI and II were similar before and after SIT, while expression levels of Foxp3 and VγIII after SIT were significantly higher than those before. Before SIT, the significant positive correlation was observed between expression levels of Foxp3 and VγI, II, III, while negative correlation was observed between Foxp3, VγIII and VAS. After SIT, the significant positive correlation between expression levels of Foxp3 and VγIII and negative correlation between Foxp3, VγIII and VAS were observed. CONCLUSIONS: Treg and Vγ subfamily T cells were in a dynamic equilibrium in AR patients before and after effective immunotherapy for one year. The early improvement of symptoms following immunotherapy might be independent of the serum sIgE content in AR patients, but associated with the reconstitution of T cell immunity.


Assuntos
Dessensibilização Imunológica , Perfilação da Expressão Gênica , Receptores de Antígenos de Linfócitos T gama-delta/genética , Rinite Alérgica Perene/genética , Rinite Alérgica Perene/terapia , Linfócitos T Reguladores/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunoglobulina E/sangue , Masculino , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Rinite Alérgica , Rinite Alérgica Perene/sangue , Rinite Alérgica Perene/imunologia , Escala Visual Analógica , Adulto Jovem
15.
Artigo em Chinês | MEDLINE | ID: mdl-38858119

RESUMO

Objective:To investigate the criteria for selecting surgical approaches for frontal and ethmoid sinus osteomas of different locations and sizes on CT imaging. Methods:Using sagittal and coronal CT images, the following lines were delineated: the F-line(a horizontal line passing nasofrontal beak), the M-line(a vertical line passing paries medialis orbitae), and the P-line(a vertical line passing the center of the pupil). Classification of frontal and ethmoid sinus osteomas was based on their relationship with these lines. Appropriate surgical approaches were selected, including pure endoscopic approaches, endoscopic combined with eyebrow incision approach, and endoscopic combined with coronal incision approach. This method was applied to a single center at the Third Affiliated Hospital of Sun Yat-sen University for endoscopic resection of frontal and ethmoid sinus osteoma. Case Data: Sixteen cases of ethmoid sinus osteomas were treated from January 2020 to September 2023. Among these cases, there were 9 males and 7 females, with ages ranging from 18 to 69 years, and a median age of 48 years. Results:Thirteen cases underwent pure endoscopic resection of the osteoma, while in three cases, a combined approach was utilized. Among the combined approach cases, two exceeded both the M-line and the F-line but did not cross the P-line; therefore, they underwent endoscopic combined with eyebrow incision approach. One case exceeded all three lines and thus underwent endoscopic combined with coronal incision. In all cases, complete resection of the osteoma was achieved as per preoperative planning, and none of the patients experienced significant postoperative complications. Conclusion:For frontal and ethmoid sinus osteomas, it is advisable to perform a thorough preoperative radiological assessment. Based on the size of the osteoma and its relationship to the three lines, an appropriate surgical approach should be chosen to optimize the diagnostic and treatment plan.


Assuntos
Endoscopia , Seio Etmoidal , Seio Frontal , Osteoma , Neoplasias dos Seios Paranasais , Tomografia Computadorizada por Raios X , Humanos , Osteoma/cirurgia , Osteoma/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Seio Frontal/cirurgia , Seio Frontal/diagnóstico por imagem , Seio Etmoidal/cirurgia , Seio Etmoidal/diagnóstico por imagem , Adolescente , Tomografia Computadorizada por Raios X/métodos , Neoplasias dos Seios Paranasais/cirurgia , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Endoscopia/métodos , Adulto Jovem
16.
Pharmazie ; 68(12): 951-4, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24400441

RESUMO

We previously showed that Adh1p participates in fluconazole (FLC) resistance in Candida albicans through a mechanism that may involve efflux pumps. We also found that the concomitant use of tetrandrine (TET) and FLC provided a synergistic action against C. albicans and that the mechanism of action could be related to inhibition of a drug efflux system. To determine whether Adh1p participates in the synergistic antifungal activity of TET against C. albicans, we performed a comparative proteomic study comparing cells treated with FLC and/or TET in FLC-sensitive CA-3 and untreated control cells. Proteins were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), and differentially expressed proteins were identified through matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF/TOF) mass spectrometry. The resulting data were searched against a C. albicans protein database. Our analyses identified six differentially expressed proteins; four (Eno1p, Adh1p, Slb1p, and Tdh1p) were down-regulated, and two (Xyl2p, and Cdc19p) were up-regulated. The Adh1p mRNA levels were consistent with the Adh1p protein levels in all of the groups. The results suggest that Adh1p participates in the synergistic antifungal activity of TET against C. albicans.


Assuntos
Álcool Desidrogenase/metabolismo , Antifúngicos/farmacologia , Benzilisoquinolinas/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Fluconazol/farmacologia , Proteômica , Candida albicans/metabolismo , Farmacorresistência Fúngica , Eletroforese em Gel Bidimensional , Proteínas Fúngicas/biossíntese , Proteínas Fúngicas/genética , Espectrometria de Massas , Reação em Cadeia da Polimerase em Tempo Real , Transcrição Gênica , Tripsina/química
17.
Int Forum Allergy Rhinol ; 13(9): 1726-1737, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36716409

RESUMO

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is predominantly characterized by nasal type 2 inflammation. The pathogenesis of this condition is complex. High levels of IL-17A are associated with eosinophil infiltration in some inflammatory diseases and contribute to the severity and insensitivity of corticosteroid therapy for chronic rhinosinusitis. METHODS: In the first experiment, we constructed a modified ECRS mouse model using four groups of mice: phosphate-buffered saline (PBS)-sensitized and nasal instillation (control); PBS-sensitized and Staphylococcus aureus enterotoxin B (SEB) nasal instillation after nasal tamponade (SEB group); ovalbumin (OVA)-sensitized and nasal instillation (OVA group); and OVA-sensitized combined with OVA and SEB nasal instillation after nasal tamponade (OVA + SEB group). In the second experiment, we examined the role of IL-17A by dividing the mice into four groups: control group; ECRS group; ECRS + anti-IL-17A group; and ECRS + IL-17A group. The latter two groups received intraperitoneal injections of anti-IL-17A antibody or IL-17A, respectively. RESULTS: We constructed a modified ECRS mouse model (OVA + SEB group), where the IL-17A levels were upregulated in the nasal sinus of ECRS mice and the IL-17A levels were significantly correlated with eosinophil infiltration. We further demonstrated that IL-17A induced type 2 inflammation and eosinophil infiltration in the ECRS group of mice. In contrast, IL-17A neutralization attenuated type 2 inflammatory cytokine secretion and eosinophil infiltration. CONCLUSION: OVA sensitization and unilateral nasal tamponade, combined with SEB and OVA alternate nasal instillation (OVA + SEB group), could be used to construct a more typical ECRS mouse model in which IL-17A enhanced the expression of type 2 cytokines and eosinophil infiltration.


Assuntos
Eosinofilia , Pólipos Nasais , Rinite , Sinusite , Animais , Camundongos , Pólipos Nasais/patologia , Inflamação , Sinusite/patologia , Citocinas/metabolismo , Ovalbumina , Doença Crônica , Eosinófilos
18.
Mediators Inflamm ; 2012: 815308, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23345934

RESUMO

Obstructive sleep apnoea syndrome (OSAS) is a chronic inflammatory disease regulated by T lymphocytes. Our purpose is to assess the pattern of Th17 cells and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in peripheral blood of patients with OSAS. Fourty-four OSAS men and 20 healthy volunteers were enrolled. Twenty-three patients were classified into mild to moderate group and 21 cases were classified into severe group according to the severity of OSAS. We detected the frequencies of Th17 and Treg and related serum cytokines secretion and expressions of key transcription factors. OSAS patients revealed significant increase in peripheral Th17 number, Th17-related cytokines (IL-17 and IL-6), and RORγt mRNA levels. They also presented a significant decrease in Treg number, Treg-related cytokines (TGF-ß(1)), and Foxp3 mRNA levels as compared with normal persons. As a result, the Th17/Treg ratios were markedly more upregulated in OSAS patients than those in control group. Furthermore, the Th17/Treg ratio was positively related to the severity of OSAS and serum levels of C-reactive protein. The development of OSAS may be associated with peripheral Th17/Treg imbalance and characterized by a proinflammatory cytokine microenvironment. These results opened an alternative explanation for the substantial activation of immune cells in OSAS and the development of related complications.


Assuntos
Apneia Obstrutiva do Sono/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Idoso , Proteína C-Reativa/análise , Citocinas/sangue , Fatores de Transcrição Forkhead/genética , Humanos , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , RNA Mensageiro/sangue , Índice de Gravidade de Doença
19.
J Asthma Allergy ; 15: 341-352, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35320987

RESUMO

Purpose: Histopathologic characterizations of central compartment atopic disease (CCAD) by whole-slide imaging remains lacking. We aim to study clinical presentations and cellular endotyping diagnosis of Chinese CCAD using artificial intelligence (AI). Methods: A total of 72 patients diagnosed with chronic rhinosinusitis with nasal polyps (CRSwNP) were enrolled. CCAD was defined by positive result of serology specific IgE, endoscopic and radiological findings. The aeroallergen sensitization status, endoscopic results, radiological findings, and symptoms were evaluated and compared between patients with CCAD (n=14), eosinophilic CRSwNP (ENP, n=32) and non-eosinophilic CRSwNP (NENP, n=26). The cellular endotypes including eosinophils, neutrophils, lymphocytes, and plasma cells were analyzed by the AI chronic rhinosinusitis evaluation platform 2.0. Results: CCAD was most common in male (71.43%). The positive rate of aeroallergen in patients with CCAD is 100%, which is much higher than those in patients with ENP (40.63%) and NENP (23.08%). Allergic rhinitis incidence was found to be 57.14% in Chinese CCAD subjects, which is obviously higher when compared with those in patients with ENP (21.88%) or NENP (0.00%). The presence of asthma was not significantly different between groups. Chinese CCAD population demonstrated mild symptoms and lower endoscopic and radiological scores than those in patients with ENP and NENP. For cellular endotypes in CCAD subjects, the median of eosinophils, neutrophils, lymphocytes, and plasma cells was 26.55%, 0.49%, 60.85%, and 7.33%, respectively. The proportion of eosinophils in nasal tissue and peripheral blood mononuclear cells from the CCAD group is between the proportions in those patients with ENP and NENP. Conclusion: Chinese CCAD was associated with aeroallergen sensitivity, and displayed an eosinophil-dominant inflammatory pattern. Thus, proper management with allergy control and topical steroids could be recommended for CCAD treatment.

20.
Allergy Asthma Immunol Res ; 14(6): 604-652, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36426395

RESUMO

In the last few decades, there has been a progressive increase in the prevalence of allergic rhinitis (AR) in China, where it now affects approximately 250 million people. AR prevention and treatment include allergen avoidance, pharmacotherapy, allergen immunotherapy (AIT), and patient education, among which AIT is the only curative intervention. AIT targets the disease etiology and may potentially modify the immune system as well as induce allergen-specific immune tolerance in patients with AR. In 2017, a team of experts from the Chinese Society of Allergy (CSA) and the Chinese Allergic Rhinitis Collaborative Research Group (C2AR2G) produced the first English version of Chinese AIT guidelines for AR. Since then, there has been considerable progress in basic research of and clinical practice for AIT, especially regarding the role of follicular regulatory T (TFR) cells in the pathogenesis of AR and the use of allergen-specific immunoglobulin E (sIgE) in nasal secretions for the diagnosis of AR. Additionally, potential biomarkers, including TFR cells, sIgG4, and sIgE, have been used to monitor the incidence and progression of AR. Moreover, there has been a novel understanding of AIT during the coronavirus disease 2019 pandemic. Hence, there was an urgent need to update the AIT guideline for AR by a team of experts from CSA and C2AR2G. This document aims to serve as professional reference material on AIT for AR treatment in China, thus improving the development of AIT across the world.

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