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1.
Nutrients ; 11(9)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466230

RESUMO

Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.


Assuntos
Imunidade Inata , Imunidade nas Mucosas , Receptores Acoplados a Proteínas-G/metabolismo , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , Infecções Respiratórias/metabolismo , Paladar , Animais , Antibacterianos/uso terapêutico , Bactérias/imunologia , Bactérias/metabolismo , Cílios/imunologia , Cílios/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Transdução de Sinais , Paladar/efeitos dos fármacos
2.
Nutrients ; 11(7)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336570

RESUMO

BACKGROUND: Although Lactobacillus casei Shirota (LcS) can benefit the immune status, the effects of LcS in the immune/inflammatory responses of marathon runners has never been evaluated. Therefore, here we evaluated the effect of daily ingestion of fermented milk containing or not LcS in the systemic and upper airway immune/inflammatory responses before and after a marathon. METHODS: Forty-two male marathon runners ingested a fermented milk containing 40 billion of LcS/day (LcS group, n = 20) or placebo (unfermented milk, n = 22) during 30 days pre-marathon. Immune/inflammatory parameters in nasal mucosa and serum, as well as concentrations of secretory IgA (SIgA) and antimicrobial peptides in saliva, were evaluated before and after fermented milk ingestion, immediately, 72 h, and 14 d post-marathon. RESULTS: Higher proinflammatory cytokine levels in serum and nasal mucosa, and also lower salivary levels of SIgA and antimicrobial peptides, were found immediately post-marathon in the placebo group compared to other time points and to LcS group. In opposite, higher anti-inflammatory levels and reduced neutrophil infiltration on nasal mucosa were found in the LcS group compared to other time points and to the placebo group. CONCLUSION: For the first time, it is shown that LcS is able to modulate the systemic and airways immune responses post-marathon.


Assuntos
Inflamação/prevenção & controle , Lactobacillus casei/classificação , Sistema Respiratório/imunologia , Corrida , Adulto , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/metabolismo , Produtos Fermentados do Leite , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoglobulina A/química , Masculino , Pessoa de Meia-Idade , Saliva/química
3.
Int Immunopharmacol ; 74: 105718, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31255882

RESUMO

Combined allergic rhinitis and asthma syndrome (CARAS) is a concept of "one airway - one disease" or "unified airway disease ". The upper and lower airway inflammation characterizes allergic rhinitis and asthma, respectively and both diseases have shown an intimate connection in their genesis, coexistence and similarities as triggered by the same etiological agents; the same inflammatory cell profile and share therapeutic treatment. This review highlights the concept of CARAS by its phenotype, endotype and biomarker classification. Indeed, rhinitis is divided into four major phenotypes: allergic rhinitis; infectious rhinitis; non-infective/non-allergic rhinitis and mixed rhinitis. On the other hand, asthma has no common consensus yet; however, the most accepted classification is based on the stage of life (early- or late- onset asthma) in which the clinical symptoms are presented. Experimental researches where animals develop a syndrome similar to CARAS have been contributed to better understand the pathogenesis of the syndrome. Therefore, the aim of this review is to clarify current terms related to CARAS as definition, phenotypes, endotypes/biomarkers, physiopathology and treatments.


Assuntos
Asma , Sistema Respiratório/imunologia , Rinite Alérgica , Animais , Biomarcadores , Modelos Animais de Doenças , Humanos , Inflamação , Fenótipo , Síndrome
4.
Immunity ; 51(1): 169-184.e5, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31231035

RESUMO

Naive CD4+ T cells differentiate into functionally diverse T helper (Th) cell subsets. Th2 cells play a pathogenic role in asthma, yet a clear picture of their transcriptional profile is lacking. We performed single-cell RNA sequencing (scRNA-seq) of T helper cells from lymph node, lung, and airways in the house dust mite (HDM) model of allergic airway disease. scRNA-seq resolved transcriptional profiles of naive CD4+ T, Th1, Th2, regulatory T (Treg) cells, and a CD4+ T cell population responsive to type I interferons. Th2 cells in the airways were enriched for transcription of many genes, including Cd200r1, Il6, Plac8, and Igfbp7, and their mRNA profile was supported by analysis of chromatin accessibility and flow cytometry. Pathways associated with lipid metabolism were enriched in Th2 cells, and experiments with inhibitors of key metabolic pathways supported roles for glucose and lipid metabolism. These findings provide insight into the differentiation of pathogenic Th2 cells in the context of allergy.


Assuntos
Asma/imunologia , Hipersensibilidade Respiratória/imunologia , Sistema Respiratório/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th2/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Modelos Animais de Doenças , Humanos , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Orexina/genética , Pyroglyphidae/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma
5.
Virol J ; 16(1): 77, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174549

RESUMO

BACKGROUND: Influenza B virus is a main causative pathogen of annual influenza epidemics, however, research on influenza B virus in general lags behind that on influenza A viruses, one of the important reasons is studies on influenza B viruses in animal models are limited. Here we investigated the tree shrew as a potential model for influenza B virus studies. METHODS: Tree shrews and ferrets were inoculated with either a Yamagata or Victoria lineage influenza B virus. Symptoms including nasal discharge and weight loss were observed. Nasal wash and respiratory tissues were collected at 2, 4 and 6 days post inoculation (DPI). Viral titers were measured in nasal washes and tissues were used for pathological examination and extraction of mRNA for measurement of cytokine expression. RESULTS: Clinical signs and pathological changes were also evident in the respiratory tracts of tree shrews and ferrets. Although nasal symptoms including sneezing and rhinorrhea were evident in ferrets infected with influenza B virus, tree shrews showed no significant respiratory symptoms, only milder nasal secretions appeared. Weight loss was observed in tree shrews but not ferrets. V0215 and Y12 replicated in all three animal (ferrets, tree shrews and mice) models with peak titers evident on 2DPI. There were no significant differences in peak viral titers in ferrets and tree shrews inoculated with Y12 at 2 and 4DPI, but viral titers were detected at 6DPI in tree shrews. Tree shrews infected with influenza B virus showed similar seroconversion and respiratory tract pathology to ferrets. Elevated levels of cytokines were detected in the tissues isolated from the respiratory tract after infection with either V0215 or Y12 compared to the levels in the uninfected control in both animals. Overall, the tree shrew was sensitive to infection and disease by influenza B virus. CONCLUSION: The tree shrew to be a promising model for influenza B virus research.


Assuntos
Anticorpos Antivirais/sangue , Modelos Animais de Doenças , Vírus da Influenza B/imunologia , Infecções por Orthomyxoviridae/imunologia , Tupaiidae/virologia , Animais , Citocinas/imunologia , Feminino , Furões , Vírus da Influenza B/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nariz/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Árvores , Carga Viral , Replicação Viral
6.
Nat Commun ; 10(1): 2288, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123265

RESUMO

Recurrent acute respiratory tract infections (ARTIs) affect a large population, yet the specific decisive factors are largely unknown. Here we study a population of 4407 children diagnosed with ARTI, comparing respiratory virome and serum cytokine profiles associated with multiple ARTIs and single ARTI during a six-year period. The relative abundance of Propionibacterium phages is significantly elevated in multiple ARTIs compared to single ARTI group. Serum levels of TIMP-1 and PDGF-BB are markedly increased in multiple ARTIs compared to single-ARTI and non-ARTI controls, making these two cytokines potential predictors for multiple ARTIs. The presence of Propionibacterium phages is associated with higher levels of TIMP-1 and PDGF-BB. Receiver operating characteristic (ROC) curve analyses show that the combination of TIMP-1, PDGF-BB and Propionibacterium phages could be a strong predictor for multiple ARTIs. These findings indicate that respiratory microbe homeostasis and specific cytokines are associated with the onset of multiple ARTIs over time.


Assuntos
Bacteriófagos/isolamento & purificação , Citocinas/sangue , Sistema Respiratório/virologia , Infecções Respiratórias/sangue , Doença Aguda , Bacteriófagos/genética , Criança , Pré-Escolar , Citocinas/imunologia , Suscetibilidade a Doenças/sangue , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/microbiologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Estudos Longitudinais , Masculino , Metagenômica/métodos , Microbiota/genética , Propionibacterium/virologia , Proteômica/métodos , Recidiva , Sistema Respiratório/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Estudos Retrospectivos
7.
Mol Immunol ; 111: 136-144, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054407

RESUMO

Production of antimicrobial peptides cathelicidins, interferons and cytokines is an important feature in airway epithelial host defense. The innate immune response to alpha-herpesvirus infection at the sites of primary replication has not been fully studied. Thus, the aim of this study was to determine the expression of innate immune components, cathelicidins, IFNß, TNFα and TNF receptors (TNFRI and TNFRII) during acute infection and reactivation of bovine herpesvirus type 1 (BoHV-1) and 5 (BoHV-5) in the respiratory tract and lymphoid tissue of their natural host. We found that BoHV infection modulates mainly the expression of BMAP28, a key cathelicidin in cattle. It was downregulated by both viruses in retropharyngeal lymph nodes of acutely infected-calves, and it was accompanied by a lower expression of IFNß, TNFα and TNFRI. BoHV-5 showed a pronounced role in the downregulation of BMAP28, even in nasal mucosa and lung. However, during reactivation, BoHV-5 upregulated both BMAP28 and IFNß in retropharyngeal lymph nodes. Acute replication induced also TNFα mRNA and protein synthesis, and expression of TNFRI and II was positively regulated during both acute infection and reactivation, particularly in the trachea. Moreover, BMAP27 was detected during BoHV-1 reactivation suggesting a potential role at this stage. Thus, cathelicidins are implicated in alpha-herpesvirus infections of the bovine respiratory system and the response is distinct during BoHV-1 and BoHV-5 acute infection and reactivation. This demonstrates that these viruses modulate differentially the components of innate immune response, possibly influencing their pathogenesis. This study provides an initial pilot analysis of factors that might be implicated in alpha-herpesvirus infection of the bovine respiratory system.


Assuntos
Catelicidinas/imunologia , Doenças dos Bovinos/imunologia , Infecções por Herpesviridae/imunologia , Herpesvirus Bovino 1/imunologia , Interferon beta/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Bovinos , Citocinas/imunologia , Infecções por Herpesviridae/veterinária , Imunidade Inata/imunologia , Projetos Piloto , RNA Mensageiro/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Regulação para Cima/imunologia
8.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061143

RESUMO

Interleukin 1 receptor-like 1 (IL1RL1), also known as suppression of tumorigenicity 2 (ST2), is the receptor for interleukin 33 (IL-33) and has been increasingly studied in type 2 inflammation. An increase in airway IL-33/ST2 signaling in asthma has been associated with eosinophilic inflammation, but little is known about the role of ST2 in neutrophilic inflammation. Airway Mycoplasma pneumoniae and human rhinovirus (HRV) infections are linked to neutrophilic inflammation during acute exacerbations of asthma. However, whether ST2 contributes to M. pneumoniae- and HRV-mediated airway inflammation is poorly understood. The current study sought to determine the functions of ST2 during airway M. pneumoniae or HRV infection. In cultured normal human primary airway epithelial cells, ST2 overexpression (OE) increased the production of neutrophilic chemoattractant IL-8 in the absence or presence of M. pneumoniae or HRV1B infection. ST2 OE also enhanced HRV1B-induced IP-10, a chemokine involved in asthma exacerbations. In the M. pneumoniae-infected mouse model, ST2 deficiency, in contrast to sufficiency, significantly reduced the levels of neutrophils following acute (≤24 h) infection, while in the HRV1B-infected mouse model, ST2 deficiency significantly reduced the levels of proinflammatory cytokines KC, IP-10, and IL-33 in bronchoalveolar lavage (BAL) fluid. Overall, ST2 overexpression in human epithelial cells and ST2 sufficiency in mice increased the M. pneumoniae and HRV loads in cell supernatants and BAL fluid. After pathogen infection, ST2-deficient mice showed a higher level of the host defense protein lactotransferrin in BAL fluid. Our data suggest that ST2 promotes proinflammatory responses (e.g., neutrophils) to airway bacterial and viral infection and that blocking ST2 signaling may broadly attenuate airway infection and inflammation.


Assuntos
Infecções por Enterovirus/imunologia , Enterovirus/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Mycoplasma pneumoniae/fisiologia , Pneumonia por Mycoplasma/microbiologia , Sistema Respiratório/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Líquido da Lavagem Broncoalveolar/virologia , Enterovirus/genética , Infecções por Enterovirus/genética , Infecções por Enterovirus/virologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Células Epiteliais/virologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Interleucina-33/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mycoplasma pneumoniae/genética , Pneumonia por Mycoplasma/genética , Pneumonia por Mycoplasma/imunologia , Sistema Respiratório/microbiologia , Sistema Respiratório/virologia
9.
PLoS Pathog ; 15(4): e1007694, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30978238

RESUMO

Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P. aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P. aeruginosa. We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1ß and IL-18 in a manner that is synergistic with P. aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P. aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a "fire alarm" to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Catelicidinas/farmacologia , Células Epiteliais/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Sistema Respiratório/imunologia , Animais , Caspase 1/metabolismo , Comunicação Celular , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo
10.
Basic Clin Pharmacol Toxicol ; 125(3): 237-252, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30861614

RESUMO

Electronic cigarettes (E-cigarettes) are considered a preferable alternative to conventional cigarettes due to the lack of combustion and the absence of tobacco-specific toxicants. E-cigarettes have rapidly gained in popularity in recent years amongst both existing smokers and previous non-smokers. However, a growing literature demonstrates that E-cigarettes are not as safe as generally believed. Here, we discuss the immunological, and other, deleterious effects of E-cigarettes on a variety of cell types and host defence mechanisms in humans and in murine models. We review not only the effects of complete E-cigarette liquids, but also each of the main components-nicotine, humectants and flavourings. This MiniReview thus highlights the possible role of E-cigarettes in the pathogenesis of disease and raises awareness of the potential harm that E-cigarettes may cause.


Assuntos
Resistência à Doença/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , Fumaça/efeitos adversos , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Resistência à Doença/imunologia , Aromatizantes/toxicidade , Humanos , Higroscópicos/toxicidade , Camundongos , Modelos Animais , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Nicotina/toxicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Produtos do Tabaco/toxicidade
11.
Mucosal Immunol ; 12(3): 589-600, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30874596

RESUMO

The respiratory tract is an important site of immune regulation; required to allow protective immunity against pathogens, while minimizing tissue damage and avoiding aberrant inflammatory responses to inhaled allergens. Several cell types work in concert to control pulmonary immune responses and maintain tolerance in the respiratory tract, including regulatory and effector T cells, airway and interstitial macrophages, dendritic cells and the airway epithelium. The cytokines transforming growth factor ß, interleukin (IL-) 10, IL-27, and IL-35 are key coordinators of immune regulation in tissues such as the lung. Here, we discuss the role of these cytokines during respiratory infection and allergic airway disease, highlighting the critical importance of cellular source and immunological context for the effects of these cytokines in vivo.


Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Pulmão/imunologia , Mucosa Respiratória/imunologia , Sistema Respiratório/imunologia , Infecções Respiratórias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Homeostase , Humanos , Tolerância Imunológica
12.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30873934

RESUMO

Streptococcus pneumoniae (the pneumoccus) is the leading cause of otitis media, community-acquired pneumonia, and bacterial meningitis. The success of the pneumococcus stems from its ability to persist in the population as a commensal and avoid killing by immune system. This chapter first reviews the molecular mechanisms that allow the pneumococcus to colonize and spread from one anatomical site to the next. Then, it discusses the mechanisms of inflammation and cytotoxicity during emerging and classical pneumococcal infections.


Assuntos
Inflamação/imunologia , Inflamação/microbiologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Sangue/imunologia , Sangue/microbiologia , Encéfalo/imunologia , Encéfalo/microbiologia , Parede Celular/imunologia , Infecções Comunitárias Adquiridas/microbiologia , Orelha Média/microbiologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feto/imunologia , Feto/microbiologia , Coração/microbiologia , Humanos , Meningites Bacterianas/microbiologia , Nasofaringe/imunologia , Nasofaringe/microbiologia , Otite Média/microbiologia , Infecções Pneumocócicas/microbiologia , Pneumonia/microbiologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Streptococcus pneumoniae/patogenicidade
13.
Allergol. immunopatol ; 47(1): 2-11, ene.-feb. 2019. graf, ilus
Artigo em Inglês | IBECS | ID: ibc-180764

RESUMO

Background: To investigate neonatal maternal separation (NMS) effects on airway inflammation of asthma and potential mechanism using a mouse model. Methods: 80 Balb/c neonatal male mice were randomly assigned to NMS and non-NMS groups. Feces were collected on PND21, 28, 35 and 42 to analyze microbiota and short-chain fatty acids (SCFAs). Non-NMS group were then divided into control (group A) and asthma groups (group B), while NMS group was assigned to NMS + asthma (group C) and NMS + SCFAs + asthma groups (group D). Inflammatory cells and eosinophils (EOS) in bronchoalveolar lavage fluid (BALF) were assessed. Pathological changes and cytokines in lung tissue were observed. Protein expression of Occludin and E-cadherin in airway epithelial was examined. Results: The number of S', diversity index H′ and dominance index D', as well as content butyric acid in NMS group C were significantly lower than non-NMS group B (p<0.05). Mice in group C had a higher level of inflammatory cells and EOS compared with group A, B and D. EOS moderate infiltration was found in mice of group B, C and D. Mice in group C had significantly higher levels of cytokines and showed slightly increased bronchial epithelium goblet cells and a small amount of visceral secretions. Occludin and E-cadherin expression in lung in B, C and D groups was depressed, and protein level in group C was significantly lower than group B and D. Conclusions: NMS is associated with exacerbated inflammation of adult asthma by changing intestinal microflora resulting in butanoic acid decline and airway epithelial barrier damage


No disponible


Assuntos
Humanos , Animais , Masculino , Feminino , Camundongos , Asma/imunologia , Eosinófilos/imunologia , Fezes/microbiologia , Inflamação/imunologia , Sistema Respiratório/imunologia , Animais Recém-Nascidos , Asma/microbiologia , Asma/psicologia , Ácido Butírico/metabolismo , Modelos Animais de Doenças , Inflamação/microbiologia , Inflamação/psicologia , Camundongos Endogâmicos BALB C
14.
Eur J Immunol ; 49(1): 144-156, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29762870

RESUMO

Influenza virus infection is an important cause of severe asthma exacerbations, but it remains unclear how a Th1-mediated antiviral response triggers a prototypical Th2 disease. We investigated CD4+ T cells and group 2 innate lymphoid cells (ILC2s) in influenza virus-infected mice. We found that ILC2s accumulated in the lung rapidly after influenza virus infection, but the induction of IL-5 and IL-13 secretion was delayed and concomitant with T cell activation. In an influenza-induced exacerbation of allergic airway inflammation model we noticed an initial reduction of ILC2 numbers and cytokine production in broncho-alveolar lavage compared to chronic house dust mite (HDM)-mediated airway inflammation alone. ILC2s phenotype was characterized by low T1/ST2, ICOS, KLRG1, and CD25 expression, resembling naïve ILC2s. The contribution of ILC2s to type 2 cytokine production in the early stage of the influenza-induced exacerbation was limited. In contrast, T cells showed increased IL-4 and IL-5 production when exposed to both HDM and influenza virus. Upon virus clearance, ILC2s regained an activated T1/ST2high ICOShigh KLRG1high CD25high phenotype paired with cytokine production and were major contributors to the type 2 cytokine milieu. Collectively, our data indicate that both T cells and ILC2s contribute to influenza-induced exacerbation of allergic airway inflammation, but with different kinetics.


Assuntos
Fator de Transcrição GATA3/metabolismo , Hipersensibilidade/imunologia , Inflamação/imunologia , Influenza Humana/imunologia , Linfócitos/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Sistema Respiratório/imunologia , Células Th2/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Células Cultivadas , Citocinas/metabolismo , Progressão da Doença , Fator de Transcrição GATA3/genética , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Pyroglyphidae
15.
FASEB J ; 33(1): 126-139, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29965797

RESUMO

The circadian clock is a critical regulator of immune function. We recently highlighted a role for the circadian clock in a mouse model of pulmonary inflammation. The epithelial clock protein Bmal1 was required to regulate neutrophil recruitment in response to inflammatory challenge. Bmal1 regulated glucocorticoid receptor (GR) recruitment to the neutrophil chemokine, CXC chemokine ligand 5 (CXCL5), providing a candidate mechanism. We now show that clock control of pulmonary neutrophilia persists without rhythmic glucocorticoid availability. Epithelial GR-null mice had elevated expression of proinflammatory chemokines in the lung under homeostatic conditions. However, deletion of GR in the bronchial epithelium blocked rhythmic CXCL5 production, identifying GR as required to confer circadian control to CXCL5. Surprisingly, rhythmic pulmonary neutrophilia persisted, despite nonrhythmic CXCL5 responses, indicating additional circadian control mechanisms. Deletion of GR in myeloid cells alone did not prevent circadian variation in pulmonary neutrophilia and showed reduced neutrophilic inflammation in response to dexamethasone treatment. These new data show GR is required to confer circadian control to some inflammatory chemokines, but that this alone is insufficient to prevent circadian control of neutrophilic inflammation in response to inhaled LPS, with additional control mechanisms arising in the myeloid cell lineage.-Ince, L. M., Zhang, Z., Beesley, S., Vonslow, R. M., Saer, B. R., Matthews, L. C., Begley, N., Gibbs, J. E., Ray, D. W., Loudon, A. S. I. Circadian variation in pulmonary inflammatory responses is independent of rhythmic glucocorticoid signaling in airway epithelial cells.


Assuntos
Ritmo Circadiano/imunologia , Células Epiteliais/imunologia , Macrófagos Peritoneais/imunologia , Neutrófilos/imunologia , Pneumonia/imunologia , Receptores de Glucocorticoides/fisiologia , Sistema Respiratório/imunologia , Animais , Células Cultivadas , Quimiocina CXCL5/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Glucocorticoides/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Transdução de Sinais
16.
Sci Total Environ ; 649: 620-628, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30176473

RESUMO

Exposure to ambient air pollution has been associated with various adverse health effects including respiratory, cardiovascular and neurological diseases. Exposure data for some specific pollutants and settings are however still insufficient and mechanisms underlying negative health outcomes are not fully elucidated. This pilot study aimed to assess individual exposure to three traffic-related air pollutants, black carbon (BC), polycyclic aromatic hydrocarbons (PAHs) and benzene, and the relationship with respiratory and oxidative stress outcomes in a cross-sectional sample of 48 green space workers in Brussels, Belgium. Participants were followed during four consecutive working days in 2016-2017 during which their individual exposure to BC, PAHs, benzene and more generally air pollution was measured using aethalometers, urinary biomarkers (1-hydroxypyrene, 1-naphthol, 2-naphthol, S-phenylmercapturic acid) and questionnaires. Data on respiratory health and oxidative stress were collected using questionnaires and respiratory/urinary biomarkers (exhaled nitric oxide [NO], 8-hydroxydeoxyguanosine [8-OHdG]). Associations between exposure and health outcomes were investigated using comparison tests and linear regression models, after stratification by present-day smoking status. Spatial variation in BC exposure was high, with concentrations varying between 0.26 and 5.69 µg/m3. The highest levels were recorded during transport and, to a lesser extent, in green spaces located in the vicinity of roads with high traffic intensity. Concentrations of PAHs and benzene biomarkers did not systematically exceed the limits of detection. Among smokers, respiratory inflammation increased linearly with exposure to BC measured over the four days of follow-up (ß = 8.73, 95% CI: 4.04, 13.41). Among non-smokers, oxidative stress increased linearly with BC measured on the fourth day (ß = 2.88, 95% CI: 1.52, 4.24). Despite some limitations, this work supports the hypothesis that BC induces respiratory inflammation and oxidative stress. It also highlights the value of this compound as well as exhaled NO and urinary 8-OHdG biomarkers to detect early/mild effects of air pollution.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Benzeno/efeitos adversos , Exposição Ambiental , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Fuligem/efeitos adversos , Emissões de Veículos/análise , Bélgica , Cidades , Estudos Transversais , Monitoramento Ambiental , Humanos , Inflamação/induzido quimicamente , Estresse Oxidativo , Projetos Piloto , Sistema Respiratório/imunologia , Sistema Respiratório/fisiopatologia , População Urbana
17.
Eur J Immunol ; 49(1): 66-78, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30365177

RESUMO

The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4+ Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4+ T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm-family-deficient CD4+ T cells had higher expression of Th1-associated genes than WT and purified naive Ifitm-family-deficient CD4+ T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology.


Assuntos
Hipersensibilidade/imunologia , Inflamação/imunologia , Proteínas de Membrana/metabolismo , Sistema Respiratório/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/genética , Células Cultivadas , Interferon gama/metabolismo , Interleucina-27/metabolismo , Interleucina-4/metabolismo , Ativação Linfocitária/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Equilíbrio Th1-Th2/genética
18.
Allergol Immunopathol (Madr) ; 47(1): 2-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30458973

RESUMO

BACKGROUND: To investigate neonatal maternal separation (NMS) effects on airway inflammation of asthma and potential mechanism using a mouse model. METHODS: 80 Balb/c neonatal male mice were randomly assigned to NMS and non-NMS groups. Feces were collected on PND21, 28, 35 and 42 to analyze microbiota and short-chain fatty acids (SCFAs). Non-NMS group were then divided into control (group A) and asthma groups (group B), while NMS group was assigned to NMS+asthma (group C) and NMS+SCFAs+asthma groups (group D). Inflammatory cells and eosinophils (EOS) in bronchoalveolar lavage fluid (BALF) were assessed. Pathological changes and cytokines in lung tissue were observed. Protein expression of Occludin and E-cadherin in airway epithelial was examined. RESULTS: The number of S', diversity index H' and dominance index D', as well as content butyric acid in NMS group C were significantly lower than non-NMS group B (p<0.05). Mice in group C had a higher level of inflammatory cells and EOS compared with group A, B and D. EOS moderate infiltration was found in mice of group B, C and D. Mice in group C had significantly higher levels of cytokines and showed slightly increased bronchial epithelium goblet cells and a small amount of visceral secretions. Occludin and E-cadherin expression in lung in B, C and D groups was depressed, and protein level in group C was significantly lower than group B and D. CONCLUSIONS: NMS is associated with exacerbated inflammation of adult asthma by changing intestinal microflora resulting in butanoic acid decline and airway epithelial barrier damage.


Assuntos
Asma/imunologia , Eosinófilos/imunologia , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Inflamação/imunologia , Sistema Respiratório/imunologia , Animais , Animais Recém-Nascidos , Asma/microbiologia , Asma/psicologia , Ácido Butírico/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/microbiologia , Inflamação/psicologia , Contagem de Leucócitos , Masculino , Privação Materna , Camundongos , Camundongos Endogâmicos BALB C , Microbiota
19.
Curr Opin Allergy Clin Immunol ; 19(1): 1-6, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30543547

RESUMO

PURPOSE OF REVIEW: Microbiome refers to the genetic potential of resident microorganisms that inhabit a given niche. The exact role of the microbiome and its relation to chronic disease processes remains largely unknown, although various associations have been observed. We reviewed current literature investigating the microbiome of the upper airway by subsite (nasal cavity, sinus cavities, nasopharynx, and larynx) and its relation to chronic inflammatory disease processes. RECENT FINDINGS: The disruption of indigenous microbiota at a specific subsite may lead to pathogen overgrowth and increased susceptibility to infection. This has previously been demonstrated in the gastrointestinal tract and lower airways. The role of the microbiome and its relation to pathogenesis of disease in the upper airway, however, is less clearly understood. The present review discusses the recent studies that appear to link dysbiosis to upper airway chronic inflammatory diseases. SUMMARY: Despite mounting research, the role of microbiota in the upper airway remains poorly understood. Based on review of the current literature comparing healthy versus diseased patients with site-specific inflammatory conditions, a complex consortium of microbial communities inhabits the upper airway. Fluctuations in the baseline microbiome may contribute to disease pathogenesis, and improved understanding of the dynamics between shifting microbiota may be critical to guiding future medical therapy.


Assuntos
Disbiose/microbiologia , Doenças do Sistema Imunitário/microbiologia , Inflamação/imunologia , Microbiota/fisiologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Animais , Terapia Biológica , Suscetibilidade a Doenças , Disbiose/imunologia , Homeostase , Humanos , Doenças do Sistema Imunitário/imunologia , Inflamação/microbiologia
20.
J Immunol ; 202(3): 871-882, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578308

RESUMO

Severe respiratory virus infections feature robust local host responses that contribute to disease severity. Immunomodulatory strategies that limit virus-induced inflammation may be of critical importance, notably in the absence of antiviral vaccines. In this study, we examined the role of the pleiotropic cytokine IL-6 in acute infection with pneumonia virus of mice (PVM), a natural rodent pathogen that is related to respiratory syncytial virus and that generates local inflammation as a feature of severe infection. In contrast to Influenza A, PVM is substantially less lethal in IL-6 -/- mice than it is in wild-type, a finding associated with diminished neutrophil recruitment and reduced fluid accumulation in lung tissue. Ly6Chi proinflammatory monocytes are recruited in response to PVM via a CCR2-dependent mechanism, but they are not a major source of IL-6 nor do they contribute to lethal sequelae of infection. By contrast, alveolar macrophages are readily infected with PVM in vivo; ablation of alveolar macrophages results in prolonged survival in association with a reduction in virus-induced IL-6. Finally, as shown previously, administration of immunobiotic Lactobacillus plantarum to the respiratory tracts of PVM-infected mice promoted survival in association with diminished levels of IL-6. We demonstrated in this study that IL-6 suppression is a critical feature of the protective mechanism; PVM-infected IL-6 -/- mice responded to low doses of L. plantarum, and administration of IL-6 overcame L. plantarum-mediated protection in PVM-infected wild-type mice. Taken together, these results connect the actions of IL-6 to PVM pathogenesis and suggest cytokine blockade as a potential therapeutic modality in severe infection.


Assuntos
Interleucina-6/imunologia , Vírus da Pneumonia Murina/imunologia , Infecções por Pneumovirus/imunologia , Animais , Inflamação , Interleucina-6/farmacologia , Lactobacillus plantarum/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Probióticos/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia
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