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1.
Medicine (Baltimore) ; 99(35): e21920, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871927

RESUMO

INTRODUCTION: Collagen colitis (CC) is a microscopic colitis diagnosed by mucosal biopsy and is extremely rare in children. PATIENT CONCERNS: We reported a child with severe persistent diarrhea that could not be relieved with traditional diarrheal treatment. No abnormalities were found after multiple colonoscopies. DIAGNOSES: A significant increase in total IgE levels was found in the patient's blood. He had a history of mild chronic allergic rhinitis and slightly intermittent wheezing. However, we found that the child had a hyperallergic reaction to multiple respiratory antigens and had mild pulmonary dysfunction. Finally, colonoscopy with biopsy identified the diagnosis of CC. INTERVENTION: Considering that a respiratory allergic reaction was one of the causes of diarrhea, anti-allergic treatment was given to the child, and his severe diarrhea was soon relieved. Corticosteroid treatment was suggested to the patient, but his parents firmly refused steroid therapy. According to the patient's specific allergic reaction to mites, desensitization treatment was finally chosen for him. OUTCOMES: After 1 year of desensitization for dust mites, the patient's respiratory symptoms improved, total IgE levels decreased, autoantibodies declined, and diarrhea did not reoccur. Colonoscopy with biopsy showed a significant improvement in pathology. CONCLUSION: CC in children is rare, and childhood CC induced by a respiratory allergic reaction has not been previously reported. Therefore, this is a special case of CC in a patient who was cured with anti-allergy treatments and desensitization instead of steroid therapy.


Assuntos
Colite Colagenosa/diagnóstico , Colite Colagenosa/etiologia , Diarreia/etiologia , Hipersensibilidade Respiratória/complicações , Antialérgicos/uso terapêutico , Biópsia , Criança , Doença Crônica , Colite Colagenosa/terapia , Colonoscopia , Dessensibilização Imunológica , Diarreia/terapia , Humanos , Masculino , Hipersensibilidade Respiratória/terapia
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(6): 793-798, 2020 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895196

RESUMO

OBJECTIVE: To explore the value of leukotriene D4 (LTD4) bronchial provocation test (BPT) in detection of airway hyper-responsiveness (AHR) in children. METHODS: A total of 151 children aged 6 to 14 years, including 86 in remission of asthma and 65 with acute bronchitis, who were followed up in our respiratory clinic between November, 2017 and August, 2018. The children were randomly divided into LTD4 group (78 cases) and methacholine (MCH) group (73 cases). In LTD4 group, the 78 children underwent LTD4-BPT, including 46 with asthma and 32 children having re-examination for previous episodes of acute bronchitis; in MCH group, the 73 children underwent MCH-BPT, including 40 with asthma and 33 with acute bronchitis. MCH-BPT was also performed in the asthmatic children in the LTD4 group who had negative responses to LTD4 after an elution period. The major adverse reactions of the children to the two BPT were recorded. The diagnostic values of the two BPT were evaluated using receiver-operating characteristic (ROC) curve. RESULTS: There was no significant difference in the results of basic lung function tests between LTD4 group and MCH group (P>0.05). The positive rate of BPT in asthmatic children in the LTD4 group was significantly lower than that in the MCH group (26.1% vs 72.5%; P < 0.05). The positive rate of BPT in children with previous acute bronchitis in the LTD4 group was lower than that in the MCH group (3.1% vs 15.2%). The positive rate of MCH-BPT in asthmatic children had negative BPT results in LTD4 group was 58.8%, and their asthma was mostly mild. The sensitivity was lower in LTD4 group than in MCH group (0.2609 vs 0.725), but the specificity was slightly higher in LTD4 group (0.9688 vs 0.8485).The area under ROC curvein LTD4 group was lower than that in MCH group (0.635 vs 0.787). In children with asthma in the LTD4 group, the main adverse reactions in BPT included cough (34.8%), shortness of breath (19.6%), chest tightness (15.2%), and wheezing (10.9%). The incidence of these adverse reactions was significantly lower in LTD4 group than in MCH group (P < 0.05). Serious adverse reactions occurred in neither of the two groups. CONCLUSIONS: LTD4-BPT had high safety in clinical application of children and was similar to the specificity of MCH-BPT. However, it had low sensitivity, low diagnostic value, and limited application value in children's AHR detection.


Assuntos
Asma , Hipersensibilidade Respiratória , Adolescente , Testes de Provocação Brônquica , Criança , Humanos , Leucotrieno D4 , Cloreto de Metacolina
3.
J Pharmacol Exp Ther ; 373(3): 476-487, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32273303

RESUMO

Zona pellucida binding protein 2 (Zpbp2) and ORMDL sphingolipid biosynthesis regulator 3 (Ormdl3), mapped downstream of Zpbp2, were identified as two genes associated with airway hyper-responsiveness (AHR). Ormdl3 gene product has been shown to regulate the biosynthesis of ceramides. Allergic asthma was shown to be associated with an imbalance between very-long-chain ceramides (VLCCs) and long-chain ceramides (LCCs). We hypothesized that Fenretinide can prevent the allergic asthma-induced augmentation of Ormdl3 gene expression, normalize aberrant levels of VLCCs and LCCs, and treat allergic asthma symptoms. We induced allergic asthma by house dust mite (HDM) in A/J WT mice and Zpbp2 KO mice expressing lower levels of Ormdl3 mRNA than WT. We investigated the effect of a novel formulation of Fenretinide, LAU-7b, on the AHR, inflammatory cell infiltration, mucus production, IgE levels, and ceramide levels. Although lower Ormdl3 expression, which was observed in Zpbp2 KO mice, was associated with lower AHR, allergic Zpbp2 KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant levels of VLCCs and LCCs induced by HDM. LAU-7b treatment protects both the Zpbp2 KO and WT mice. The treatment significantly lowers the gene expression of Ormdl3, normalizes the VLCCs and LCCs, and corrects all the other phenotypes associated with allergic asthma after HDM challenge, except the elevated levels of IgE. LAU-7b treatment prevents the augmentation of Ormdl3 expression and ceramide imbalance induced by HDM challenge and protects both WT and Zpbp2 KO mice against allergic asthma symptoms. SIGNIFICANCE STATEMENT: Compared with A/J WT mice, KO mice with Zpbp2 gene deletion have lower AHR and lower levels of Ormdl3 expression. The novel oral clinical formulation of Fenretinide (LAU-7b) effectively lowers the AHR and protects against inflammatory cell infiltration and mucus accumulation induced by house dust mite in both Zpbp2 KO and WT A/J mice. LAU-7b prevents Ormdl3 overexpression in WT allergic mice and corrects the aberrant levels of very-long-chain and long-chain ceramides in both WT and Zpbp2 KO allergic mice.


Assuntos
Asma/tratamento farmacológico , Asma/metabolismo , Ceramidas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fenretinida/farmacologia , Proteínas de Membrana/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Knockout , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo
4.
Toxicol Appl Pharmacol ; 395: 114981, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32240662

RESUMO

What factors and underlying mechanisms influence the occurrence of the atopic march remain unclear. Recent studies suggest that exposure to diisononyl phthalate (DINP) might be associated with the occurrence of atopic dermatitis (AD) and asthma. However, little is known about the role of DINP exposure in the atopic march. In this study, we investigated the effect of DINP exposure on the progression from AD to asthma, and explored the potential mechanisms. We built an atopic march mouse model from AD to asthma, by exposure to DINP and sensitization with OVA. Pyrrolidine dithiocarbamate and SB203580 were used to block NF-κB and p38 MAPK respectively, to explore the possible molecular mechanisms. The data showed that DINP aggravated airway remodeling and airway hyperresponsiveness (AhR) in the progression from AD to asthma, induced a sharp increase in IL-33, IgE, Th2 and Th17 cytokines, and resulted in an increase in the expression of thymic stromal lymphopoietin (TSLP) and in the number of inflammatory cells. Blocking NF-κB inhibited AD-like lesions, and the production of IL-33 and TSLP in the progression of AD, while alleviating airway remodeling, AhR, and the expression of Th2 and Th17 cytokines in both the progression of AD and the asthmatic phenotype. Blocking p38 MAPK in the progression of asthma, inhibited airway remodeling, AhR, and the expression of Th2 and Th17 cytokines. The results demonstrated that exposure to DINP enhanced the immune response to memory CD4+ T helper cells through the NF-κB and p38 MAPK signaling pathways, leading to an aggravation of the atopic march.


Assuntos
Hipersensibilidade Imediata/induzido quimicamente , NF-kappa B/fisiologia , Ácidos Ftálicos/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Citocinas/biossíntese , Dermatite Atópica/induzido quimicamente , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , Ovalbumina/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Células Th17/imunologia , Células Th2/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
5.
Ecotoxicol Environ Saf ; 195: 110491, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32213367

RESUMO

Epidemiological studies have reported short-term fine particulate matter (PM2.5) exposure to increase incidence of asthma, related to the increase of airway hyperresponsiveness (AHR); however, the underlying mechanism remains unclear. Aim of this study was to elucidate the role of kallikrein in PM2.5-induced airway hyperresponsiveness and understand the underlying mechanism. Nose-only PM2.5 exposure system was used to generate a mouse model of airway hyperresponsiveness. Compared with the control group, PM2.5 exposure could significantly increase airway resistance, lung inflammation, kallikrein expression of bronchi-lung tissue and bradykinin (BK) secretion. However, these changes could be alleviated by kallikrein inhibitor. In addition,PM2.5 could increase the viability of human airway smooth muscle cells (hASMCs), accompanied by increased expression of kallikrein 14 (Klk14), bradykinin 2 receptor (B2R), bradykinin secretion and cytosol calcium level, while kallikrein 14 gene knockdown could significantly amelioratethe above response induced by PM2.5. Taken together, the data suggested kallikrein to play a key role in PM2.5-induced airway hyperresponsiveness, and that it could be a potential therapeutic target in asthma.


Assuntos
Poluentes Atmosféricos/toxicidade , Bradicinina/metabolismo , Calicreínas/metabolismo , Material Particulado/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/patologia , Tamanho da Partícula , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais
6.
Environ Sci Pollut Res Int ; 27(14): 17250-17257, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32152860

RESUMO

An air sampling study was conducted to evaluate personal formaldehyde exposures in a group of office workers spread across five geographical locations in the USA. Passive badge samples for formaldehyde were collected on three participants in each location, as well as in the office and home indoor microenvironments of each participant over 3 individual days. Median personal 24-h formaldehyde concentrations ranged from 9.9 to 18 µg/m3. Personal 24-h formaldehyde concentrations in one location were significantly higher than concentrations measured in the other four locations; no significant differences existed between any of the other locations. The participants in this study spent an average of 53% of their daily time in their homes, 36% at their office, and 11% in other indoor and outdoor locations. A comparison of measured 24-h personal formaldehyde concentrations and a model of average exposure based upon measured concentrations in the indoor microenvironments suggested that both the home and office formaldehyde concentrations were a strong predictor (R2 = 0.88) of overall personal exposure. The data from this study are representative of office workers in urban environments and can be used as background formaldehyde exposure levels (in the absence of specific sources) for both occupational and nonoccupational exposure assessments.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Exposição Ambiental/análise , Monitoramento Ambiental , Formaldeído/efeitos adversos , Formaldeído/análise , Humanos , Hipersensibilidade Respiratória , Inquéritos e Questionários , Estados Unidos
7.
Chemosphere ; 248: 126035, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32014637

RESUMO

Epidemiologic studies show that there is a link between Bisphenol A (BPA) exposure and lung inflammation. Despite this, the molecular mechanisms are not entirely known. This study sought to determine whether exposure to BPA affected the development of ovalbumin (OVA) induced lung inflammation in adolescent female mice and whether the mechanism was related to mTOR-mediated autophagy pathway. Female 4-week-old C57BL/6 mice after one week of domestication were randomly divided into five groups (8/group): control group, OVA group, 0.1 µg mL-1 BPA + OVA group, 0.2 µg mL-1 BPA + OVA group and 0.4 µg mL-1 BPA + OVA group. BPA exacerbated airway hyperresponsiveness (AHR), induced the pathological changes in the lung, which also enhanced inflammatory cells and cytokine levels. In addition, BPA exposure affected expression of autophagy associated proteins and genes. This research results indicated that BPA aggravated OVA-induced lung inflammation and induced abnormal immune function in mice, and its mechanism was related to the activation of autophagy pathway by down-regulation expression of mTOR. These findings suggest that therapeutic strategies to target autophagy may offer a new approach for severe asthma therapy.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Pneumonia/induzido quimicamente , Animais , Asma/induzido quimicamente , Autofagia , Citocinas/metabolismo , Feminino , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina , Pneumonia/patologia , Hipersensibilidade Respiratória , Serina-Treonina Quinases TOR/metabolismo , Testes de Toxicidade
8.
Am J Respir Cell Mol Biol ; 62(4): 503-512, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913653

RESUMO

Ozone causes airway hyperresponsiveness, a defining feature of asthma. We have reported that the gut microbiome contributes to sex differences in ozone-induced airway hyperresponsiveness. Altering dietary fiber affects the gut microbiome. The purpose of this study was to determine the effects of dietary fiber on pulmonary responses to ozone and whether these effects differ by sex. We fed male and female mice fiber-free diets or diets enriched in one of two types of dietary fiber, cellulose and pectin, for 3 days before ozone exposure. Compared with control diets or pectin-enriched diets, cellulose-enriched diets attenuated ozone-induced airway hyperresponsiveness in male but not female mice. In contrast, fiber-free diets augmented responses to ozone in female but not male mice. Analysis of 16S rRNA sequencing of fecal DNA also indicated sex differences in the impact of dietary fiber on the gut microbiome and identified bacterial taxa that were associated with ozone-induced airway hyperresponsiveness. Our data suggest that microbiome-based therapies such as prebiotics may provide an alternative therapeutic strategy for air pollution-triggered asthma, but they indicate that such therapeutics may need to be tailored differently for males and females.


Assuntos
Fibras na Dieta/metabolismo , Pulmão/efeitos dos fármacos , Ozônio/farmacologia , Animais , Asma/metabolismo , Dieta/métodos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/metabolismo , Hipersensibilidade Respiratória/metabolismo , Caracteres Sexuais
9.
Am J Physiol Lung Cell Mol Physiol ; 318(3): L459-L471, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913654

RESUMO

We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Ácido Hialurônico/farmacologia , Músculo Liso/efeitos dos fármacos , Receptores de Detecção de Cálcio/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico , Viscossuplementos/farmacologia , Animais , Bromo/toxicidade , Células Cultivadas , Cloretos/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Músculo Liso/metabolismo , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/genética , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia
10.
Am J Respir Cell Mol Biol ; 62(5): 657-667, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31922900

RESUMO

Cystic fibrosis (CF) is a lethal genetic disease characterized by progressive lung damage and airway obstruction. The majority of patients demonstrate airway hyperresponsiveness (AHR), which is associated with more rapid lung function decline. Recent studies in the neonatal CF pig demonstrated airway smooth muscle (ASM) dysfunction. These findings, combined with observed CF transmembrane conductance regulator (CFTR) expression in ASM, suggest that a fundamental defect in ASM function contributes to lung function decline in CF. One established driver of AHR and ASM dysfunction is transforming growth factor (TGF) ß1, a genetic modifier of CF lung disease. Prior studies demonstrated that TGFß exposure in CF mice drives features of CF lung disease, including goblet cell hyperplasia and abnormal lung mechanics. CF mice displayed aberrant responses to pulmonary TGFß, with elevated PI3K signaling and greater increases in lung resistance compared with controls. Here, we show that TGFß drives abnormalities in CF ASM structure and function through PI3K signaling that is enhanced in CFTR-deficient lungs. CF and non-CF mice were exposed intratracheally to an adenoviral vector containing the TGFß1 cDNA, empty vector, or PBS only. We assessed methacholine-induced AHR, bronchodilator response, and ASM area in control and CF mice. Notably, CF mice demonstrated enhanced AHR and bronchodilator response with greater ASM area increases compared with non-CF mice. Furthermore, therapeutic inhibition of PI3K signaling mitigated the TGFß-induced AHR and goblet cell hyperplasia in CF mice. These results highlight a latent AHR phenotype in CFTR deficiency that is enhanced through TGFß-induced PI3K signaling.


Assuntos
Fibrose Cística/enzimologia , Fibrose Cística/fisiopatologia , Fosfatidilinositol 3-Quinases/metabolismo , Hipersensibilidade Respiratória/enzimologia , Hipersensibilidade Respiratória/fisiopatologia , Transdução de Sinais , Fator de Crescimento Transformador beta/efeitos adversos , Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Animais , Broncoconstrição/efeitos dos fármacos , Células Caliciformes/patologia , Hiperplasia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Transdução de Sinais/efeitos dos fármacos
11.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L242-L251, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31746625

RESUMO

Eosinophils mediate airway hyperresponsiveness by increasing vagally mediated reflex bronchoconstriction. Here, we tested whether circulating or airway eosinophils change nerve function. Airway resistance in response to aerosolized 5-hydroxytryptamine (5-HT, 10-300 mM) was measured in wild-type mice or transgenic mice that overexpress IL5 in T cells (+IL5T), overexpress IL5 in airway epithelium (+IL5AE), or overexpress IL5 but are devoid of eosinophils (+IL5AE/-Eos). Inflammatory cells in bronchoalveolar lavage (BAL), blood, and bone marrow were quantified. Blood eosinophils were increased in +IL5T and +IL5AE mice compared with wild-type mice. +IL5T mice had increased eosinophils in bone marrow while +IL5AE mice had increased eosinophils in BAL. Eosinophils surrounding large airways were significantly increased only in +IL5AE mice. With intact vagal innervation, aerosolized 5-HT significantly increased airway resistance in +IL5AE mice. 5-HT-induced bronchoconstriction was blocked by vagotomy or atropine, demonstrating that it was mediated via a vagal reflex. Airway resistance was not increased in +IL5AE/-Eos mice, demonstrating that it required lung eosinophils, but was not affected by increased bone marrow or blood eosinophils or by increased IL5 in the absence of eosinophils. Eosinophils did not change M3 function on airway smooth muscle, since airway responses to methacholine in vagotomized mice were not different among strains. Eosinophils surrounding large airways were sufficient, even in the absence of increased IL5 or external insult, to increase vagally mediated reflex bronchoconstriction. Specifically blocking or reducing eosinophils surrounding large airways may effectively inhibit reflex hyperresponsiveness mediated by vagus nerves in eosinophilic asthma.


Assuntos
Broncoconstrição , Eosinófilos/patologia , Pulmão/patologia , Pulmão/fisiopatologia , Reflexo , Nervo Vago/patologia , Resistência das Vias Respiratórias , Animais , Medula Óssea/patologia , Lavagem Broncoalveolar , Contagem de Células , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Eosinofilia Pulmonar/metabolismo , Eosinofilia Pulmonar/patologia , Eosinofilia Pulmonar/fisiopatologia , Receptor Muscarínico M3/metabolismo , Hipersensibilidade Respiratória/fisiopatologia , Serotonina , Vagotomia
12.
Environ Toxicol Pharmacol ; 73: 103273, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31629203

RESUMO

Cerium dioxide nanoparticles (CeO2NPs) have been used as diesel fuel-borne catalysts for improved efficiency and pollutant emissions. Concerns that such material may influence diesel exhaust particle (DEP) effects within the lung upon inhalation, prompted us to examine particle responses in mice in the presence and absence of the common allergen house dust mite (HDM). Repeated intranasal instillation of combined HDM and DEP increased airway mucin, eosinophils, lymphocytes, IL-5, IL-13, IL-17A and plasma IgE, which were further increased with CeO2NPs co-exposure. A single co-exposure of CeO2NPs and DEP after repeated HDM exposure increased macrophage and IL-17A levels above DEP induced levels. CeO2NPs exposure in the absence of HDM also resulted in increased levels of plasma IgE and airway mucin staining, changes not observed with repeated DEP exposure alone. These observations indicate that CeO2NPs can modify exhaust particulate and allergen induced inflammatory events in the lung with the potential to influence conditions such as allergic airway disease.


Assuntos
Cério/toxicidade , Nanopartículas/toxicidade , Pyroglyphidae , Hipersensibilidade Respiratória , Emissões de Veículos/toxicidade , Alérgenos , Animais , Poeira , Inflamação , Interleucina-17 , Pulmão/imunologia , Camundongos , Material Particulado
13.
Toxicol Lett ; 321: 146-154, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31836503

RESUMO

BACKGROUND: Exposure to particulate matters (PMs) can lead to an acute exacerbation of allergic airway diseases, increasing the severity of symptoms and mortality. However, little is known about the underlying molecular mechanism. This study aimed to investigate the effects of PMs on acute exacerbation of allergic airway inflammation and seek potential therapeutic targets. METHODS: Non-allergic control and ovalbumin (OVA)-allergic wide-type (WT) and Toll-like receptor 2 knockout (Tlr2-/-) mice were exposed to 100 µg of PM (diameter 5.85 µm) or saline by the oropharyngeal instillation. The responses were examined three days after exposure. In the RAW264.7 macrophage cell line, Tlr2 was knocked down by small-interfering RNA or the NF-κB inhibitor JSH-23 was used, and then the cells were stimulated with PMs for 12 h before comparison of the inflammatory responses. RESULTS: PM exposure led to increased inflammatory cell recruitment and airway intensity of PAS + staining in OVA-allergic WT mice, accompanied with an accumulation of inflammatory cells and elevated inflammatory cytokines, such as IL-6 and IL-18, in the bronchoalveolar lavage fluid (BALF). Furthermore, the protein levels of TLR2 and the NLRP3 inflammasome were elevated concomitantly with the airway inflammation post-OVA/PMs challenge. Tlr2 deficiency effectively inhibited the airway inflammation, including pulmonary inflammatory cell recruitment, mucus secretion, serum OVA-specific immunoglobulin E (IgE), and BALF inflammatory cytokine production. Additionally, the P-induced NLRP3 activation in the RAW 264.7 cell line was diminished by the knockdown of Tlr2 or JSH-23 treatment in vitro. CONCLUSION: Our results indicated that PMs exacerbate the allergic airway inflammation mediated by the TLR2/ NF-κB/NLRP3 signaling pathway. Inhibition of NF-κB seems to be a possible treatment.


Assuntos
Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Material Particulado/toxicidade , Hipersensibilidade Respiratória/induzido quimicamente , Receptor 2 Toll-Like/metabolismo , Alérgenos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Pulmão/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Tamanho da Partícula , Células RAW 264.7 , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética
14.
J Immunol ; 204(3): 682-693, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31871023

RESUMO

Eosinophilia is a hallmark of allergic airway inflammation (AAI). Identifying key molecules and specific signaling pathways that regulate eosinophilic inflammation is critical for development of novel therapeutics. Tropomycin receptor kinase A (TrkA) is the high-affinity receptor for nerve growth factor. AAI is associated with increased expression of TrkA by eosinophils; however, the functional role of TrkA in regulating eosinophil recruitment and contributing to AAI is poorly understood. This study identifies, to our knowledge, a novel mechanism of eotaxin-mediated activation of TrkA and its role in regulating eosinophil recruitment by using a chemical-genetic approach to specifically inhibit TrkA kinase activity with 1-NM-PP1 in TrkAF592A-knock-in (TrkA-KI) eosinophils. Blockade of TrkA by 1-NM-PP1 enhanced eosinophil spreading on VCAM-1 but inhibited eotaxin-1 (CCL11)-mediated eosinophil migration, calcium flux, cell polarization, and ERK1/2 activation, suggesting that TrkA is an important player in the signaling pathway activated by eotaxin-1 during eosinophil migration. Further, blockade of matrix metalloprotease with BB-94 inhibited eotaxin-1-induced TrkA activation and eosinophil migration, additively with 1-NM-PP1, indicating a role for matrix metalloproteases in TrkA activation. TrkA inhibition in Alternaria alternata-challenged TrkA-KI mice markedly inhibited eosinophilia and attenuated various features of AAI. These findings are indicative of a distinctive eotaxin-mediated TrkA-dependent signaling pathway, which, in addition to other TrkA-activating mediators, contributes to eosinophil recruitment during AAI and suggests that targeting the TrkA signaling pathway to inhibit eosinophil recruitment may serve as a therapeutic strategy for management of eosinophilic inflammation in allergic airway disease, including asthma.


Assuntos
Alternaria/fisiologia , Alternariose/imunologia , Asma/imunologia , Eosinófilos/imunologia , Hipersensibilidade/imunologia , Receptor trkA/metabolismo , Hipersensibilidade Respiratória/imunologia , Animais , Movimento Celular , Células Cultivadas , Quimiocina CCL11/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Mutantes , Mutação/genética , Receptor trkA/genética , Transdução de Sinais
15.
Respir Physiol Neurobiol ; 271: 103290, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525465

RESUMO

Airway remodeling is a key pathological lesion in chronic obstructive pulmonary disease (COPD), and it leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective at controlling airway remodeling. To address this issue, we queried the Connectivity Map (cMap) database to screen for drug candidates that had the potential to dilate the bronchus and inhibit airway smooth muscle (ASM) proliferation. We identified ciprofibrate as a drug candidate. Ciprofibrate inhibited cigarette smoke extract-induced rat ASM cell contraction and proliferation in vitro. We exposed Sprague-Dawley (SD) rats to clean air or cigarette smoke (CS) and treated the rats with ciprofibrate. Ciprofibrate improved pulmonary function, inhibited airway hypercontraction, and ameliorated morphological small airway remodeling, including airway smooth muscle proliferation, in CS-exposed rats. Ciprofibrate also significantly reduced IL-1ß, IL-12p70, IL-17A and IL-18 expression, which are related to airway remodeling, in the sera of CS-exposed rats. These findings indicate that ciprofibrate could attenuate airway remodeling in CS-exposed rats.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Fumar Cigarros/efeitos adversos , Ácidos Fíbricos/farmacologia , Exposição por Inalação/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Ácidos Fíbricos/uso terapêutico , Masculino , Técnicas de Cultura de Órgãos , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
16.
Biomed Pharmacother ; 121: 109584, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31766098

RESUMO

AIM OF THE STUDY: To develop a novel anti-asthma drug. DFSG is a novel herbal cocktail composed of 4 types of herbal medicines. This study explored whether DFSG has the potential to attenuate asthma symptom severity and aimed to determine the immunomodulatory mechanism of DFSG using a chronic asthmatic mouse model induced by repeated challenges with Dermatogoides pteronyssinus (Der p). MATERIALS AND METHODS: BALB/c mice were intratracheally inoculated with Der p (50 µl, 1 mg/ml) once a week for 5 weeks. In addition, 30 min before Der p challenge, the mice were orally administered 1x DFSG (1 g/kg) or 1/2x DFSG (0.5 g/kg). Three days after the final challenge, the mice were sacrificed to evaluate inflammatory cell infiltration, lung histological features, blood total IgE, and cytokine levels in pulmonary alveolar lavage fluid. Furthermore, 30 min after the addition of DFSG, caffeic acid, p-coumaric acid or chlorogenic acid to A549 cells, 10 ng/ml IL-1ß was added to evaluate the effect of the drug on mucin 5AC (MUC5AC) gene expression after stimulation of A549 cells by IL-1ß. RESULTS: DFSG significantly reduced Der p-induced airway hyperresponsiveness, bronchial inflammatory cell infiltration, and total IgE and IgG1 serum levels. Furthermore, DFSG significantly inhibited TH2 cytokines and increased the expression of TH1 cytokines. In addition, immunohistochemical staining demonstrated that DFSG inhibited MUC5AC expression in the bronchial epithelial cells. DFSG and a mixture of caffeic acid, p-coumaric acid, and chlorogenic acid inhibited MUC5AC gene expression in A549 cells after stimulation with IL-1ß. CONCLUSION: These results suggest that by regulating TH1 and TH2 cytokines and MUC5AC expression, DFSG exhibits anti-airway inflammatory cell infiltration and anti-hyperresponsiveness activity and inhibits specific immunity in a chronic asthmatic mouse model. Therefore, DFSG has potential for development into a drug for chronic asthma treatment.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Mucina-5AC/metabolismo , Células A549 , Animais , Antiasmáticos/farmacologia , Antígenos de Dermatophagoides/toxicidade , Asma/induzido quimicamente , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucina-5AC/antagonistas & inibidores , Distribuição Aleatória , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo
17.
PLoS One ; 14(12): e0226442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31887143

RESUMO

Chronic irritating cough in patients with allergic disorders may reflect behavioral or reflex response that is inappropriately matched to the stimulus present in the respiratory tract. Such dysregulated response is likely caused by sensory nerve damage driven by allergic mediators leading to cough hypersensitivity. Some indirect findings suggest that even acid-sensitive, capsaicin-insensitive A-δ fibers called "cough receptors" that are likely responsible for protective reflex cough may be modulated through immune driven inflammation. The aim of this study was to find out whether protective reflex cough is altered during acute allergic airway inflammation in rabbits sensitized to ovalbumin. In order to evaluate the effect of such inflammation exclusively on protective reflex cough, C-fiber mediated cough was silenced using general anesthesia. Cough provocation using citric acid inhalation and mechanical stimulation of trachea was realized in 16 ovalbumin (OVA) sensitized, anesthetized and tracheotomised rabbits 24h after OVA (OVA group, n = 9) or saline challenge (control group, n = 7). Number of coughs provoked by citric acid inhalation did not differ between OVA and control group (12,2 ±6,1 vs. 17,9 ± 6,9; p = 0.5). Allergic airway inflammation induced significant modulation of cough threshold (CT) to mechanical stimulus. Mechanically induced cough reflex in OVA group was either up-regulated (subgroup named "responders" CT: 50 msec (50-50); n = 5 p = 0.003) or down-regulated (subgroup named "non responders", CT: 1200 msec (1200-1200); n = 4 p = 0.001) when compared to control group (CT: 150 msec (75-525)). These results advocate that allergen may induce longer lasting changes of reflex cough pathway, leading to its up- or down-regulation. These findings may be of interest as they suggest that effective therapies for chronic cough in allergic patients should target sensitized component of both, reflex and behavioral cough.


Assuntos
Ácido Cítrico/efeitos adversos , Tosse/imunologia , Ovalbumina/efeitos adversos , Reflexo/imunologia , Hipersensibilidade Respiratória/imunologia , Administração por Inalação , Anestesia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Tosse/sangue , Tosse/induzido quimicamente , Modelos Animais de Doenças , Eosinófilos/metabolismo , Feminino , Contagem de Leucócitos , Masculino , Coelhos , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/terapia
18.
Respir Res ; 20(1): 285, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852500

RESUMO

BACKGROUND: ß2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear. METHODS: We established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement. RESULTS: We found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 µM, and ESI-09 promoted SOCE of ASMCs at 10 µM and 100 µM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365. CONCLUSIONS: Our results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.


Assuntos
Remodelação das Vias Aéreas , Asma/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Apoptose , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/fisiopatologia , Sinalização do Cálcio , Proliferação de Células , Células Cultivadas , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Modelos Animais de Doenças , Feminino , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/genética , Hidrazonas/farmacologia , Mediadores da Inflamação/metabolismo , Isoxazóis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos BALB C , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ovalbumina , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Pneumonia/prevenção & controle , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/fisiopatologia
19.
J Pharmacol Sci ; 141(4): 139-145, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31744690

RESUMO

Type 1 regulatory T (Tr1) cells are CD4+ T cells that produce a large amount of IL-10, an anti-inflammatory cytokine. However, it has not been fully elucidated whether Tr1 cells suppress allergic asthma. In this study, the effects of adoptive transfer of in vitro-induced Tr1 cells on allergic asthma were evaluated. Splenocytes from ovalbumin (OVA)-sensitized BALB/c mice were cultured with OVA, IL-21, IL-27, and TGF-ß. After culture, IL-10-producing CD4+ T cells were isolated by Dynabeads mouse CD4 and IL-10 secretion assay, and analyzed by flow cytometry. Purified Tr1 cells (IL-10+ CD4+ T cells) were intravenously injected into OVA-sensitized BALB/c mice. The recipient mice were intratracheally challenged with OVA. Airway hyperresponsiveness to methacholine was assessed by the forced oscillation technique, followed by bronchoalveolar lavage (BAL). Almost all of the induced IL-10-producing CD4+ T cells were negative for interferon-γ, IL-4, IL-17A, and forkhead box P3, suggesting that the cells were Tr1 cells. The adoptive transfer of Tr1 cells significantly suppressed the development of airway hyperresponsiveness, and increases in IL-5, eosinophils, and neutrophils in BAL fluid. In conclusion, we demonstrated that Tr1 cells suppressed allergic asthma in mice.


Assuntos
Transferência Adotiva , Anti-Inflamatórios/metabolismo , Ovalbumina/metabolismo , Hipersensibilidade Respiratória/terapia , Linfócitos T Reguladores/metabolismo , Animais , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Resultado do Tratamento
20.
PLoS One ; 14(11): e0224163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31675376

RESUMO

The angiotensin-(1-7) [Ang-(1-7)]/MAS1 receptor signaling axis is a key endogenous anti-inflammatory signaling pathway. However, the mechanisms by which its mediates the anti-inflammatory effects are not completely understood. Using an allergic murine model of asthma, we investigated whether Ang-1(1-7)/MAS1 receptor axis a): inhibits allergic inflammation via modulation of Src-dependent transactivation of the epidermal growth factor receptor (EGFR) and downstream signaling effectors such as ERK1/2, and b): directly inhibits neutrophil and/or eosinophil chemotaxis ex vivo. Ovalbumin (OVA)-induced allergic inflammation resulted in increased phosphorylation of Src kinase, EGFR, and ERK1/2. In addition, OVA challenge increased airway cellular influx, perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyperresponsiveness (AHR). Treatment with Ang-(1-7) inhibited phosphorylation of Src kinase, EGFR, ERK1/2, the cellular and histopathological changes and AHR. Ang-(1-7) treatment also inhibited neutrophil and eosinophil chemotaxis ex vivo. These changes were reversed following pre-treatment with A779. These data show that the anti-inflammatory actions of Ang-(1-7)/ MAS1 receptor axis are mediated, at least in part, via inhibition of Src-dependent transactivation of EGFR and downstream signaling molecules such as ERK1/2. This study therefore shows that inhibition of the Src/EGRF/ERK1/2 dependent signaling pathway is one of the mechanisms by which the Ang-(1-7)/ MAS1 receptor axis mediates it anti-inflammatory effects in diseases such as asthma.


Assuntos
Angiotensina I/metabolismo , Asma/metabolismo , Receptores ErbB/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Hipersensibilidade Respiratória/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , Animais , Western Blotting , Líquido da Lavagem Broncoalveolar/citologia , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Imunofluorescência , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade Respiratória/patologia
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