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1.
Nutrients ; 13(10)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34684394

RESUMO

Bitter taste receptors (T2Rs) are G-protein-coupled receptors (GPCRs) expressed on the tongue but also in various locations throughout the body, including on motile cilia within the upper and lower airways. Within the nasal airway, T2Rs detect secreted bacterial ligands and initiate bactericidal nitric oxide (NO) responses, which also increase ciliary beat frequency (CBF) and mucociliary clearance of pathogens. Various neuropeptides, including neuropeptide tyrosine (neuropeptide Y or NPY), control physiological processes in the airway including cytokine release, fluid secretion, and ciliary beating. NPY levels and/or density of NPYergic neurons may be increased in some sinonasal diseases. We hypothesized that NPY modulates cilia-localized T2R responses in nasal epithelia. Using primary sinonasal epithelial cells cultured at air-liquid interface (ALI), we demonstrate that NPY reduces CBF through NPY2R activation of protein kinase C (PKC) and attenuates responses to T2R14 agonist apigenin. We find that NPY does not alter T2R-induced calcium elevation but does reduce T2R-stimulated NO production via a PKC-dependent process. This study extends our understanding of how T2R responses are modulated within the inflammatory environment of sinonasal diseases, which may improve our ability to effectively treat these disorders.


Assuntos
Mucosa Nasal/metabolismo , Neuropeptídeo Y/fisiologia , Óxido Nítrico/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Apigenina/farmacologia , Cálcio/metabolismo , Células Cultivadas , Cílios/fisiologia , Humanos , Neuropeptídeo Y/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Proteína Quinase C/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Rinite/metabolismo , Sinusite/metabolismo
2.
Physiol Rep ; 9(20): e15075, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34676696

RESUMO

Exercise has substantial health benefits, but the effects of exercise on immune status and susceptibility to respiratory infections are less clear. Furthermore, there is limited research examining the effects of prolonged exercise on local respiratory immunity and antiviral activity. To assess the upper respiratory tract in response to exercise, we collected nasal lavage fluid (NALF) from human subjects (1) at rest, (2) after 45 min of moderate-intensity exercise, and (3) after 180 min of moderate-intensity exercise. To assess immune responses of the lower respiratory tract, we utilized a murine model to examine the effect of exercise duration on bronchoalveolar lavage (BAL) fluid immune cell content and lung gene expression. NALF cell counts did not change after 45 min of exercise, whereas 180 min significantly increased total cells and leukocytes in NALF. Importantly, fold change in NALF leukocytes correlated with the post-exercise fatigue rating in the 180-min exercise condition. The acellular portion of NALF contained strong antiviral activity against Influenza A in both resting and exercise paradigms. In mice undergoing moderate-intensity exercise, BAL total cells and neutrophils decreased in response to 45 or 90 min of exercise. In lung lobes, increased expression of heat shock proteins suggested that cellular stress occurred in response to exercise. However, a broad upregulation of inflammatory genes was not observed, even at 180 min of exercise. This work demonstrates that exercise duration differentially alters the cellularity of respiratory tract fluids, antiviral activity, and gene expression. These changes in local mucosal immunity may influence resistance to respiratory viruses, including influenza or possibly other pathogens in which nasal mucosa plays a protective role, such as rhinovirus or SARS-CoV-2.


Assuntos
Exercício Físico/fisiologia , Vírus da Influenza A/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Líquido da Lavagem Nasal/imunologia , Neutrófilos/imunologia , Adolescente , Adulto , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Expressão Gênica , Humanos , Leucócitos/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Lavagem Nasal/métodos , Líquido da Lavagem Nasal/citologia , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Neutrófilos/metabolismo , Fatores de Tempo , Adulto Jovem
3.
Tohoku J Exp Med ; 255(1): 19-25, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497164

RESUMO

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


Assuntos
Inflamação/etiologia , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Poluentes Atmosféricos/química , Poluentes Atmosféricos/toxicidade , Animais , Feminino , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Exposição por Inalação , Malondialdeído/metabolismo , Modelos Animais , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Tamanho da Partícula , Material Particulado/química , Ratos , Ratos Sprague-Dawley
4.
Life Sci ; 284: 119922, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34480930

RESUMO

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


Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/metabolismo , Receptor Notch2/metabolismo , Rinite Alérgica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Inflamação/patologia , Lentivirus/metabolismo , Camundongos Endogâmicos C57BL , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Receptor Notch2/sangue , Rinite Alérgica/sangue , Índice de Gravidade de Doença , Transcrição Genética
5.
Nat Commun ; 12(1): 5621, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556667

RESUMO

Although serological studies have shown that antibodies against SARS-CoV-2 play an important role in protection against (re)infection, the dynamics of mucosal antibodies during primary infection and their potential impact on viral load and the resolution of disease symptoms remain unclear. During the first pandemic wave, we assessed the longitudinal nasal antibody response in index cases with mild COVID-19 and their household contacts. Nasal and serum antibody responses were analysed for up to nine months. Higher nasal receptor binding domain and spike protein-specific antibody levels at study inclusion were associated with lower viral load. Older age was correlated with more frequent COVID-19 related symptoms. Receptor binding domain and spike protein-specific mucosal antibodies were associated with the resolution of systemic, but not respiratory symptoms. Finally, receptor binding domain and spike protein-specific mucosal antibodies remained elevated up to nine months after symptom onset.


Assuntos
Anticorpos Neutralizantes/análise , Anticorpos Antivirais/análise , COVID-19/diagnóstico , Mucosa Nasal/metabolismo , SARS-CoV-2/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Teste Sorológico para COVID-19/estatística & dados numéricos , Criança , Humanos , Imunidade nas Mucosas , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Índice de Gravidade de Doença , Carga Viral , Adulto Jovem
6.
Sci Rep ; 11(1): 15927, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354210

RESUMO

Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.


Assuntos
COVID-19/imunologia , Mucosa Nasal/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , COVID-19/genética , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Celular , Imunidade Inata , Lactente , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma , Adulto Jovem
7.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445093

RESUMO

The airway epithelium of the human nasal mucosa acts as a physical barrier that protects against inhaled substances and pathogens via bicellular and tricellular tight junctions (bTJs and tTJs) including claudins, angulin-1/LSR and tricellulin. High mobility group box-1 (HMGB1) increased by TGF-ß1 is involved in the induction of nasal inflammation and injury in patients with allergic rhinitis, chronic rhinosinusitis, and eosinophilic chronic rhinosinusitis. However, the detailed mechanisms by which this occurs remain unknown. In the present study, to investigate how HMGB1 affects the barrier of normal human nasal epithelial cells, 2D and 2.5D Matrigel culture of primary cultured human nasal epithelial cells were pretreated with TGF-ß type I receptor kinase inhibitor EW-7197 before treatment with HMGB1. Knockdown of angulin-1/LSR downregulated the epithelial barrier. Treatment with EW-7197 decreased angulin-1/LSR and concentrated the expression at tTJs from bTJs and increased the epithelial barrier. Treatment with a binder to angulin-1/LSR angubindin-1 decreased angulin-1/LSR and the epithelial barrier. Treatment with HMGB1 decreased angulin-1/LSR and the epithelial barrier. In 2.5D Matrigel culture, treatment with HMGB1 induced permeability of FITC-dextran (FD-4) into the lumen. Pretreatment with EW-7197 prevented the effects of HMGB1. HMGB1 disrupted the angulin-1/LSR-dependent epithelial permeability barriers of HNECs via TGF-ß signaling in HNECs.


Assuntos
Proteína HMGB1/metabolismo , Mucosa Nasal/metabolismo , Transdução de Sinais , Junções Íntimas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Mucosa Nasal/citologia
8.
Sci Rep ; 11(1): 15991, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362948

RESUMO

This study was conducted to explore the roles and related mechanisms of lncRNA-TCONS_00147848 (TCONS_00147848) in nasal mucosa cell apoptosis and allergic rhinitis (AR). AR mice were sensitized with ovalbumin (OVA), with the TCONS_00147848 interference lentiviral vector (TCONS_00147848 shRNA) and FOSL2 overexpressing lentiviral vectors (pCDH-FOSL2) constructed respectively. NC shRNA, TCONS_00147848 shRNA and TCONS_00147848 shRNA + pCDH-FOSL2 were transfected into AR mice and mice with TNF-α induced nasal mucosa cells. The allergic reaction symptoms were evaluated by scoring. And in this study, we used Hematoxylin-Eosin (HE) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to detect the histological changes of nasal mucosa and apoptosis of nasal mucosa epithelial cells in mice, cell counting kit-8 (CCK-8) assay, Transwell and annexin V/PI to detect proliferation, migration and apoptosis of nasal mucosa cells of mice, respectively, enzyme-linked immunosorbent assay (ELISA) to detect the expression of inflammatory factors, qRT-PCR to detect TCONS_00147848 expression, Western blot assay to detect the expressions of FOSL2, JAK-2, STAT3, p-STAT3, BAX and BCL-2, RNA-binding protein immunoprecipitation (RIP) assay, RNA pull down assay and Co-immunoprecipitation (CoIP) assay to identify TCONS_00147848 targeting FOSL2. All these findings above reveal that knocking down TCONS_00147848 can reduce the allergic reaction symptom score of AR mice and the inflammatory reaction. The expression of IgE, IL-4, IL-5, IL-10, IL-9, IFN-γ and TNF-α in serum decreased. The expression of FOSL2, JAK-2, p-STAT3 and BAX in nasal mucosa and nasal mucosa cells of mice decreased as well, but BCL-2 expression increased. In addition, koncking down TCONS_00147848 can also inhibit the apoptosis of TNF-α induced nasal mucosa cells in mice and promote cell proliferation and migration. However, FOSL2 overexpression neutralized the effect of TCONS_00147848 shRNA. In nasal mucosa cells of mice, TCONS_00147848 can target FOSL2, interacting with STAT3. Inhibition of TCONS_00147848 can regulate JAK/STAT3 signaling pathway and reduce inflammatory response in AR mice.


Assuntos
Apoptose , Antígeno 2 Relacionado a Fos/antagonistas & inibidores , Janus Quinase 1/metabolismo , Mucosa Nasal/patologia , RNA Interferente Pequeno/genética , Rinite Alérgica/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Animais , Antígeno 2 Relacionado a Fos/genética , Janus Quinase 1/genética , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/metabolismo , RNA Interferente Pequeno/administração & dosagem , Rinite Alérgica/etiologia , Rinite Alérgica/metabolismo , Rinite Alérgica/patologia , Fator de Transcrição STAT3/genética
9.
PLoS Pathog ; 17(8): e1009890, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34460865

RESUMO

Aluminum hydroxide salts (alum) have been added to inactivated vaccines as safe and effective adjuvants to increase the effectiveness of vaccination. However, the exact cell types and immunological factors that initiate mucosal immune responses to alum adjuvants are unclear. In this study, the mechanism of action of alum adjuvant in nasal vaccination was investigated. Alum has been shown to act as a powerful and unique adjuvant when added to a nasal influenza split vaccine in mice. Alum is cytotoxic in the alveoli and stimulates the release of damage-associated molecular patterns, such as dsDNA, interleukin (IL)-1α, and IL-33. We found that Ag-specific IgA antibody (Ab) production was markedly reduced in IL-33-deficient mice. However, no decrease was observed in Ag-specific IgA Ab production with DNase I treatment, and no decrease was observed in IL-1α/ß or IL-6 production in IL-33-deficient mice. From the experimental results of primary cultured cells and immunofluorescence staining, although IL-1α was secreted by alveolar macrophage necroptosis, IL-33 release was observed in alveolar epithelial cell necroptosis but not in alveolar macrophages. Alum- or IL-33-dependent Ag uptake enhancement and elevation of OX40L expression were not observed. By stimulating the release of IL-33, alum induced Th2 immunity via IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) and increased MHC class II expression in antigen-presenting cells (APCs) in the lung. Our results suggest that IL-33 secretion by epithelial cell necroptosis initiates APC- and ILC2-mediated T cell activation, which is important for the enhancement of Ag-specific IgA Ab production by alum.


Assuntos
Hidróxido de Alumínio/química , Células Epiteliais Alveolares/imunologia , Imunoglobulina A/metabolismo , Vacinas contra Influenza/administração & dosagem , Interleucina-33/fisiologia , Infecções por Orthomyxoviridae/imunologia , Células Th2/imunologia , Adjuvantes Imunológicos/administração & dosagem , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/virologia , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Feminino , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Imunoglobulina A/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Nasal/química , Mucosa Nasal/metabolismo , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Vacinação
10.
PLoS One ; 16(8): e0255480, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34383804

RESUMO

OBJECTIVE: To explore the regulation of microRNA-29a (miR-29a) on FOS in human nasal epithelial cells and its molecular mechanism, as well as the effects of miR-29a on the cell proliferation and apoptosis. METHODS: By cell transfection, gene silencing, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry and TUNEL assay (for cell apoptosis), CCK-8 assay (for cell proliferation), dual-luciferase reporter gene assay and Western Blot, it was validated that miR-29a promoted the proliferation of human nasal epithelial cells and inhibited their apoptosis by down-regulating FOS expression in RPMI2650 and HNEpC cell lines. RESULTS: ①Compared with healthy controls, miR-29a expression was up-regulated and FOS mRNA expression was down-regulated in the nasal tissues from the patients with allergic rhinitis (AR). ②MiR-29a over-expression promoted the proliferation of RPMI2650 cells and HNEpC cells but inhibited their apoptosis. ③MiR-29a targeted at FOS. ④MiR-29a over-expression and FOS silencing both significantly promoted cell proliferation and inhibited cell apoptosis. After transfection with both miR-29a and FOS, there was a decrease in the proliferation but an increase in the apoptosis of cells.⑤MiR-29a promoted the proliferation of human nasal epithelial cells and inhibited their apoptosis by down-regulating FOS expression. CONCLUSION: MiR-29a-/FOS axis can be regarded as a potential marker and a new therapy for AR.


Assuntos
Apoptose , Células Epiteliais/patologia , Regulação da Expressão Gênica , MicroRNAs/genética , Mucosa Nasal/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Rinite Alérgica/patologia , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Células Epiteliais/metabolismo , Humanos , Mucosa Nasal/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Rinite Alérgica/genética , Rinite Alérgica/metabolismo
11.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204226

RESUMO

FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics' intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.


Assuntos
Produtos Biológicos/administração & dosagem , Antígenos de Histocompatibilidade Classe I/metabolismo , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Receptores Fc/metabolismo , Animais , Produtos Biológicos/metabolismo , Transporte Biológico , Biomarcadores , Sistemas de Liberação de Medicamentos , Expressão Gênica , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Ligação Proteica , Receptores Fc/química , Receptores Fc/genética , Transcitose
12.
Sci Rep ; 11(1): 14352, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253806

RESUMO

Some clinical situations require the use of oxygen therapy for a few hours without hypoxemia. However, there are no literature reports on the effects of acute oxygen therapy on the nasal mucosa. This study aimed to evaluate the acute effects of cold bubble humidification or dry oxygen on nasal Inflammation, oxidative stress, mucociliary clearance, and nasal symptoms. This is a randomized controlled cross-sectional study in which healthy subjects were randomly allocated into four groups: (1) CA + DRY (n = 8): individuals receiving dry compressed air; (2) OX + DRY (n = 8): individuals receiving dry oxygen therapy; (3) CA + HUMID (n = 7): individuals receiving cold bubbled humidified compressed air; (4) OX + HUMID (n = 8): individuals receiving cold bubbled humidified oxygen therapy. All groups received 3 L per minute (LPM) of the oxygen or compressed air for 1 h and were evaluated: total and differential cells in the nasal lavage fluid (NLF), exhaled nitric oxide (eNO), 8-iso-PGF2α levels, saccharin transit test, nasal symptoms, and humidity of nasal cannula and mucosa. Cold bubble humidification is not able to reduced nasal inflammation, eNO, oxidative stress, mucociliary clearance, and nasal mucosa moisture. However, subjects report improvement of nasal dryness symptoms (P < 0.05). In the conclusion, cold bubble humidification of low flow oxygen therapy via a nasal cannula did not produce any effect on the nasal mucosa and did not attenuate the oxidative stress caused by oxygen. However, it was able to improve nasal symptoms arising from the use of oxygen therapy.


Assuntos
Inflamação/metabolismo , Mucosa Nasal/metabolismo , Adulto , Estudos Transversais , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Mucosa Nasal/patologia , Neutrófilos/metabolismo , Estresse Oxidativo/fisiologia , Adulto Jovem
13.
Virology ; 561: 65-68, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34157565

RESUMO

The global COVID-19 pandemic caused by SARS-CoV-2 predominantly affects the elderly. Differential expression of SARS-CoV-2 entry genes may underlie the variable susceptibility in different patient groups. Here, we examined the gene expression of key SARS-CoV-2 entry factors in mucosal biopsies to delineate the roles of age and existing chronic airway disease. A significant inverse correlation between ACE2 and age and a downregulation of NRP1 in patients with airway disease were noted. These results indicate that the interplay between various factors may influence susceptibility and the disease course.


Assuntos
COVID-19/genética , COVID-19/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Mucosa Nasal/metabolismo , Mucosa Nasal/virologia , SARS-CoV-2/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Biomarcadores , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Internalização do Vírus , Adulto Jovem
14.
Front Immunol ; 12: 663626, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093555

RESUMO

Allergic rhinitis (AR) is a common disorder affecting up to 40% of the population worldwide and it usually persists throughout life. Nasal epithelial barrier constitutes the first line of defense against invasion of harmful pathogens or aeroallergens. Cell junctions comprising of tight junctions (TJs), adherens junctions, desmosomes and hemidesmosomes form the nasal epithelial barrier. Impairment of TJ molecules plays causative roles in the pathogenesis of AR. In this review, we describe and discuss the components of TJs and their disruption leading to development of AR, as well as regulation of TJs expression by epigenetic changes, neuro-immune interaction, epithelial-derived cytokines (thymic stromal lymphopoietin, IL-25 and IL-33), T helper 2 (Th2) cytokines (IL-4, IL-5, IL-6 and IL-13) and innate lymphoid cells. These growing evidence support the development of novel therapeutic approaches to restore nasal epithelial TJs expression in AR patients.


Assuntos
Suscetibilidade a Doenças , Mucosa Nasal/metabolismo , Rinite Alérgica/etiologia , Rinite Alérgica/metabolismo , Junções Íntimas/metabolismo , Alérgenos/imunologia , Animais , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Meio Ambiente , Epigenômica , Expressão Gênica , Humanos , Imunidade Inata , Linfócitos/imunologia , Linfócitos/metabolismo , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Neuroimunomodulação , Rinite Alérgica/patologia , Junções Íntimas/patologia
15.
Sci Rep ; 11(1): 13259, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168212

RESUMO

Urban particulate matter (UPM) is an important trigger of airway inflammation. The cross-talk between the external and internal matrix in the respiratory tract occurs due to the transepithelial network of macrophages/dendritic cells. This study characterized the immune processes induced by the epithelium after UPM exposure in special regard to interactions with monocyte-derived dendritic cells (moDCs) and monocyte-derived macrophages (moMφs) in obstructive lung diseases. A triple-cell co-culture model (8 controls, 10 asthma, and 8 patients with COPD) utilized nasal epithelial cells, along with moMφs, and moDCs was exposed to UPM for 24 h. The inflammatory response of nasal epithelial cells to UPM stimulation is affected differently by cell-cell interactions in healthy people, asthma or COPD patients of which the interactions with DCs had the strongest impact on the inflammatory reaction of epithelial cells after UPM exposure. The epithelial remodeling and DCs dysfunction might accelerate the inflammation after air pollution exposure in asthma and COPD.


Assuntos
Asma/induzido quimicamente , Células Dendríticas/efeitos dos fármacos , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Material Particulado/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Estudos Prospectivos
16.
Aging (Albany NY) ; 13(11): 14552-14556, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115612

RESUMO

SARS-CoV-2 more readily affects the elderly, especially as they present co-morbidities. In the COVID-19 pathogeny, ACE2 appears to be the key cell receptor for SARS-CoV-2 to infect humans. The level of ACE2 gene expression influences the susceptibility of contracting SARS-CoV-2. In circumstances in which the ACE2 level is low, the incidence of Covid-19 seems to be fewer. Two clinical patterns illustrate this observation, i. e., in infants and in Alzheimer's disease (AD). Very young children and AD patients get little COVID-19, in part probably due to decreased expression of ACE2. The determination of the nasal level of ACE2 gene expression could provide a useful scale to predict the susceptibility to contract the SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/etiologia , SARS-CoV-2/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , COVID-19/metabolismo , Cérebro/metabolismo , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Lactente , Mucosa Nasal/metabolismo
17.
Front Immunol ; 12: 530488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936025

RESUMO

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


Assuntos
Inflamação/genética , MicroRNAs/genética , Pólipos Nasais/genética , Rinite/genética , Sinusite/genética , Adolescente , Adulto , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Doença Crônica , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Adulto Jovem
18.
Am J Respir Cell Mol Biol ; 65(4): 366-377, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33989148

RESUMO

Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smoking-induced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker patients with asthma were analyzed. Differential gene expression and DNA methylation analyses were conducted comparing current smokers with ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking-relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. A total of 809 genes and 18,814 CpG sites were differentially associated with current smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites with a methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1, and CYP1B1. The methylation status of CpG sites altered by current smoking reversed with 1 year of smoking cessation. We confirm that current smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of patients with asthma, which is partially reversible in bronchial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.


Assuntos
Asma/genética , Metilação de DNA/genética , Expressão Gênica/genética , Mucosa Nasal/metabolismo , Fumar/efeitos adversos , Adulto , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Epigênese Genética/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fumantes
19.
Mol Med Rep ; 24(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34036391

RESUMO

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammation­mediated disease of the nasal mucosa. P2X7R has been reported to be a potential biomarker for inflammation. The aim of the present study was to explore the role of P2X7R in CRSwNP, and the interaction between P2X7R and the NLRP3 inflammasome in the development of CRSwNP. Firstly, the expression profiles of P2X7R in nasal mucosa were investigated using western blotting (WB), polymerase chain reaction (PCR) and immunofluorescence (IF) staining. Next, the effect of inflammatory stimulation with lipopolysaccharides (LPS) combined with 2'(3')­O­(4­benzoylbenzoyl) adenosine 5'­triphosphate triethylammonium salt (BzATP) on primary human nasal epithelial cells (HNECs) was determined. Then, the therapeutic effect of the selective P2X7R antagonist, A740003, on P3X7R, NOD­like receptor pyrin domain containing 3 (NLRP3) inflammasome and IL­1ß alterations in HNECs was explored using enzyme­linked immunosorbent assay, WB and PCR. It was found that P2X7R was overexpressed in CRSwNP, especially in eosinophilic CRSwNP, the expression of P2X7R, NLRP3 and IL­1ß were upregulated in HNECs after induction by LPS combined with BzATP; but the expression of NLRP3 and IL­1ß were downregulated after stimulation with A740003. The aforementioned results indicate that P2X7R­mediated NLRP3 inflammasome activation may have a role in the pathogenesis of CRSwNP.


Assuntos
Eosinófilos/metabolismo , Pólipos Nasais/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/toxicidade , Adulto , Idoso , Doença Crônica , Células Epiteliais/metabolismo , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Pólipos Nasais/complicações , Cultura Primária de Células , Receptores Purinérgicos P2X7/genética , Rinite/complicações , Sinusite/complicações , Adulto Jovem
20.
Am J Physiol Lung Cell Mol Physiol ; 321(1): L119-L129, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009038

RESUMO

In vitro biomarkers to assess cystic fibrosis transmembrane conductance regulator activity are desirable for precision modulator selection and as a tool for clinical trials. Here, we describe an organoid swelling assay derived from human nasal epithelia using commercially available reagents and equipment and an automated imaging process. Cells were collected in nasal brush biopsies, expanded in vitro, and cultured as spherical organoids or as monolayers. Organoids were used in a functional swelling assay with automated measurements and analysis, whereas monolayers were used for short-circuit current measurements to assess ion channel activity. Clinical data were collected from patients on modulators. Relationships between swelling data and short-circuit current, as well as between swelling data and clinical outcome measures, were assessed. The organoid assay measurements correlated with short-circuit current measurements for ion channel activity. The functional organoid assay distinguished individual responses as well as differences between groups. The organoid assay distinguished incremental drug responses to modulator monotherapy with ivacaftor and combination therapy with ivacaftor, tezacaftor, and elexacaftor. The swelling activity paralleled the clinical response. In conclusion, an in vitro biomarker derived from patients' cells can be used to predict responses to drugs and is likely to be useful as a preclinical tool to aid in the development of novel treatments and as a clinical trial outcome measure for a variety of applications, including gene therapy or editing.


Assuntos
Aminofenóis/farmacologia , Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/metabolismo , Indóis/farmacologia , Mucosa Nasal/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Pirrolidinas/farmacologia , Quinolonas/farmacologia , Estudos de Casos e Controles , Agonistas dos Canais de Cloreto/farmacologia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Transporte de Íons , Mutação , Mucosa Nasal/efeitos dos fármacos , Organoides/efeitos dos fármacos , Organoides/metabolismo
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