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1.
Life Sci ; 247: 117446, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32081662

RESUMO

AIMS: Previous studies showed a close relationship between obesity and asthma. In this study, we investigated the expression of endoplasmic reticulum (ER) stress genes in the lung tissue of obese ovalbumin (OVA)-sensitized male and female rats. MAIN METHODS: The rats were divided into eight groups (n = 5 per group) as follows: female and male rats fed with normal diet (FND and MND, respectively), female and male OVA-sensitized rats fed with normal diet (F-OND and M-OND, respectively), female and male rats fed with high-fat diet (F-HFD and M-HFD, respectively), female and male OVA-sensitized rats fed with high-fat diet (F-OHFD and M-OHFD, respectively). All rats were fed with a high-fat diet or standard pelts for 8 weeks, and for another 4 weeks, they were sensitized by OVA or saline. At the end of the study, lung tissue NF-kB protein level was assessed, and ER stress markers genes expression was determined by Real Time-PCR. KEY FINDING: OVA-sensitization and diet-induced obesity caused the curve of methacholine concentration-response to shift to the left. In addition, the results indicated that the EC50 (the effective concentration of methacholine generating 50% of peak response) in F-OHFD rats was statistically lower than that of the M-OHFD group (p < 0.05). Moreover, the results showed that diet-induced obesity increased the expression of ATF4, ATF6, GRP78, XBP-1, and CHOP as well as the protein level of NF-kB in this experimental model of asthma, markedly in the F-OHFD group. SIGNIFICANCE: The results suggest that ER stress may be involved in the pathogenesis of asthma observed in obese OVA-sensitized rats, especially in the female animals.


Assuntos
Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Leptina/metabolismo , NF-kappa B/metabolismo , Ovalbumina/metabolismo , Animais , Asma/metabolismo , Dieta Hiperlipídica , Retículo Endoplasmático/genética , Feminino , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/metabolismo , Pulmão , Masculino , Proteínas de Membrana/metabolismo , Cloreto de Metacolina/metabolismo , NF-kappa B/genética , Obesidade/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Fatores de Tempo
2.
Int J Vitam Nutr Res ; 90(1-2): 141-150, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30789805

RESUMO

Anti-inflammatory effect of Curcuma longa (C. longa) was shown previously. In the present study, the effect of the plant on tracheal responsiveness and lung pathological features in ovalbumin-sensitized rats was evaluated. Six groups of rats including control (C), ovalbumin (OVA)-sensitized (S), S groups treated with C. longa (CL; 0.75, 1.50, and 3.00 mg/ml equal to 150, 300 and 600 mg/kg/day) and dexamethasone (D; 1.25 µg/ml) were studied (n=8 in each group). The extract of C. longa and dexamethasone were administered with daily drinking water of animals during sensitization period (for 21 days). Following the treatment period, tracheal responsiveness to methacholine and ovalbumin and lung pathological features was investigated. Tracheal responsiveness to methacholine and OVA and lung pathological scores were increased in group S compared to controls (p<0.01 to p<0.001); however, these parameters in groups treated with dexamethasone and two higher concentrations of C. longa were significantly decreased compared to group S (p<0.05 to p<0.001). Tracheal responsiveness to methacholine was decreased from 50 to 400% due to the extract treatment. All concentrations of C. longa significantly decreased interstitial fibrosis compared to group S (p<0.05 to p<0.001). Treatment with the extract resulted to improvement of pathological changes from 20 to 70%. These results showed a preventive effect for C. longa extract on tracheal responsiveness and lung pathological insults in sensitized rats which were similar or even more than those of dexamethasone at used concentrations.


Assuntos
Curcuma , Pulmão/efeitos dos fármacos , Cloreto de Metacolina/farmacologia , Extratos Vegetais , Traqueia/efeitos dos fármacos , Animais , Pulmão/patologia , Cloreto de Metacolina/química , Ovalbumina , Extratos Vegetais/farmacologia , Ratos , Traqueia/patologia
3.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614422

RESUMO

Neurotensin (NT) demonstrates ambiguous activity on inflammatory processes. The present study was undertaken to test the potential anti-inflammatory activity of NT in a murine model of non-atopic asthma and to establish the contribution of NTR1 receptors. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by intratracheal hapten provocation. The mice were treated intraperitoneally with NT, SR 142948 (NTR1 receptor antagonist) + NT or NaCl. Twenty-four hours after the challenge, airway responsiveness to nebulized methacholine was measured. Bronchoalveolar lavage fluid (BALF) and lungs were collected for biochemical and immunohistological analysis. NT alleviated airway hyperreactivity and reduced the number of inflammatory cells in BALF. These beneficial effects were inhibited by pretreatment with the NTR1 antagonist. Additionally, NT reduced levels of IL-13 and TNF-α in BALF and IL-17A, IL12p40, RANTES, mouse mast cell protease and malondialdehyde in lung homogenates. SR 142948 reverted only a post-NT TNF-α decrease. NT exhibited anti-inflammatory activity in the hapten-induced asthma. Reduced leukocyte accumulation and airway hyperresponsiveness indicate that this beneficial NT action is mediated through NTR1 receptors. A lack of effect by the NTR1 blockade on mast cell activation, oxidative stress marker and pro-inflammatory cytokine production suggests that other pathways can be involved, which requires further research.


Assuntos
Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Haptenos/efeitos adversos , Neurotensina/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Asma/induzido quimicamente , Asma/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Cloreto de Metacolina/administração & dosagem , Cloreto de Metacolina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Neurotensina/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia
4.
Neumol. pediátr. (En línea) ; 14(3): 175-179, sept. 2019. tab
Artigo em Espanhol | LILACS | ID: biblio-1087789

RESUMO

This document updates the recommendations of the bronchial challenge test with methacholine in children. It is based primarily on the recommendations contained in the guide on the technical standard of the bronchial challenge test for methacholine from the European Society of Respiratory Diseases. The main change is the recommendation to use PD20 (methacholine dose that causes a 20% drop in FEV1) instead of PC20 (methacholine concentration that causes a 20% drop in FEV1), which allows for comparable results when different devices and different protocols are used.


Este documento actualiza las recomendaciones de la prueba de provocación bronquial con metacolina en niños. Se basa fundamentalmente en las recomendaciones contenidas en la guía sobre el estándar técnico de la prueba de provocación bronquial de metacolina de la Sociedad Europea de Enfermedades Respiratorias. El principal cambio es la recomendación de utilizar la PD20 (dosis de metacolina que provoca una caída de 20% del VEF1) en vez de PC20 (concentración de metacolina que provoca una caída del 20% en el VEF1), lo cual permite tener resultados comparables cuando se usan diferentes dispositivos y diferentes protocolos.


Assuntos
Humanos , Criança , Testes de Provocação Brônquica/métodos , Cloreto de Metacolina/administração & dosagem , Hiper-Reatividade Brônquica/diagnóstico , Hiper-Reatividade Brônquica/fisiopatologia
5.
Respir Res ; 20(1): 165, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340811

RESUMO

BACKGROUND: Complement factor C5 can either aggravate or attenuate the T-helper type 2 (TH2) immune response and airway hyperresponsiveness (AHR) in murine models of allergic asthma. The effect of C5 during the effector phase of allergen-induced asthma is ill-defined. OBJECTIVES: We aimed to determine the effect of C5 blockade during the effector phase on the pulmonary TH2 response and AHR in a house dust mite (HDM) driven murine asthma model. METHODS: BALB/c mice were sensitized and challenged repeatedly with HDM via the airways to induce allergic lung inflammation. Sensitized mice received twice weekly injections with a blocking anti-C5 or control antibody 24 h before the first challenge. RESULTS: HDM challenge in sensitized mice resulted in elevated C5a levels in bronchoalveolar lavage fluid. Anti-C5 administered to sensitized mice prior to the first HDM challenge prevented this rise in C5a, but did not influence the influx of eosinophils or neutrophils. While anti-C5 did not impact the recruitment of CD4 T cells upon HDM challenge, it reduced the proportion of TH2 cells recruited to the airways, attenuated IL-4 release by regional lymph nodes restimulated with HDM ex vivo and mitigated the plasma IgE response. Anti-C5 did not affect innate lymphoid cell (ILC) proliferation or group 2 ILC (ILC2) differentiation. Anti-C5 attenuated HDM induced AHR in the absence of an effect on lung histopathology, mucus production or vascular leak. CONCLUSIONS: Generation of C5a during the effector phase of HDM induced allergic lung inflammation contributes to TH2 cell differentiation and AHR without impacting ILC2 cells.


Assuntos
Asma/imunologia , Complemento C5a/antagonistas & inibidores , Complemento C5a/imunologia , Imunidade Inata/imunologia , Pyroglyphidae/imunologia , Células Th2/imunologia , Animais , Asma/induzido quimicamente , Asma/prevenção & controle , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imunidade Inata/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Células Th2/efeitos dos fármacos
6.
J Anim Physiol Anim Nutr (Berl) ; 103(5): 1578-1584, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31148265

RESUMO

Asthma is a chronic inflammatory lung disease of the airway; the incidence and prevalence of asthma remain high worldwide. Astragaloside IV (AS-IV) is the main active constituent of Astragalus membranaceus. Accumulating evidence suggests that AS-IV possesses anti-inflammatory and anti-asthmatic ability, but the potential molecular mechanism is required to further clarify. In this study, the anti-asthmatic effects of AS-IV on mice with ovalbumin (OVA)-induced allergic inflammation were analysed. We analysed airway hyperresponsiveness (AHR), numbers of inflammatory cells, inflammation situation in lung tissue and cytokines level in bronchoalveolar lavage fluid (BALF) between OVA-induced mice with and without AS-IV treatment. Moreover, we explored the possible signalling pathway behind the anti-asthmatic effects. Our results revealed that AS-IV treatment ameliorates airway inflammation and AHR in an OVA-induced asthma model. Besides, AS-IV treatment inhibits the interleukin (IL)-4, -5 and -13 production, and further study indicated that AS-IV treatment downregulates the expression level of p-JAK2/p-STAT6 proteins. Taken together, the present study suggested that the inhibitory effects of AS-IV on asthma therapy are at least partially involved in inhibiting the JAK2/STAT6 signalling pathway.


Assuntos
Asma/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Janus Quinase 2/metabolismo , Fator de Transcrição STAT6/metabolismo , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Janus Quinase 2/genética , Leucócitos/fisiologia , Masculino , Cloreto de Metacolina/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Parassimpatomiméticos/toxicidade , Fator de Transcrição STAT6/genética
8.
BMC Pulm Med ; 19(1): 94, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097027

RESUMO

BACKGROUND: Physical activity is an important part of life, and hence exercise-induced bronchoconstriction (EIB) can reduce the quality of life. A standardized test is needed to diagnose EIB. The American Thoracic Society (ATS) guidelines recommend an exercise challenge in combination with dry air. We investigated the feasibility of a new, ATS guidelines conform exercise challenge in a cold chamber (ECC) to detect EIB. The aim of this study was to investigate the surrogate marker reaction to methacholine, ECC and exercise challenge in ambient temperature for the prediction of a positive reaction and to re-evaluate the reproducibility of the response to an ECC. METHODS: Seventy-eight subjects aged 6 to 40 years with suspected EIB were recruited for the study. The subjects performed one methacholine challenge, two ECCs, and one exercise challenge at an ambient temperature. To define the sensitivity and specificity of the predictor, a receiver-operating characteristic curve was plotted. The repeatability was evaluated using the method described by Bland and Altman (95% Limits of agreement). RESULTS: The following cut-off values showed the best combination of sensitivity and specificity: the provocation dose causing a 20% decrease in the forced expiratory volume in 1 s (PD20FEV1) of methacholine: 1.36 mg (AUC 0.69, p < 0.05), the maximal decrease in FEV1 during the ECC: 8.5% (AUC 0.78, p < 0.001) and exercise challenges at ambient temperatures: FEV1 5.2% (AUC 0.64, p = 0.13). The median decline in FEV1 was 14.5% (0.0-64.2) during the first ECC and 10.7% (0.0-52.5) during the second ECC. In the comparison of both ECCs, the Spearman rank correlation of the FEV1 decrease was r = 0.58 (p < 0.001). The 95% limits of agreement (95% LOAs) for the FEV1 decrease were - 17.7 to 26.4%. CONCLUSIONS: The surrogate markers PD20FEV1 of methacholine and maximal decrease in FEV1 during ECC can predict a positive reaction in another ECC, whereas the maximal FEV1 decrease in an exercise challenge at an ambient temperature was not predictive. Compared with previous studies, we can achieve a similar reproducibility with an ECC. CLINICAL TRIAL REGISTRATION: NCT02026492 (retrospectively registered 03/Jan/2014).


Assuntos
Hiper-Reatividade Brônquica/diagnóstico , Broncoconstrição , Broncoconstritores , Teste de Esforço , Cloreto de Metacolina , Adolescente , Adulto , Asma Induzida por Exercício/diagnóstico , Testes de Provocação Brônquica , Criança , Estudos Cross-Over , Feminino , Volume Expiratório Forçado , Alemanha , Humanos , Masculino , Qualidade de Vida , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
10.
Iran J Allergy Asthma Immunol ; 18(1): 48-61, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30848573

RESUMO

Epidemiological and clinical studies have demonstrated a close association between obesity and asthma. The current study investigated the effect of high-fat diet on tracheal responsiveness to methacholine and insulin resistance in ovalbumin (OVA) sensitized male and female rats. The rats were divided into eight groups (n=6 per group): female with the normal diet (F+ND), male with the normal diet (M+ND), female OVA-sensitized with the normal diet (F+SND), male OVA-sensitized with the normal diet (M+SND), female with high-fat diet (F+HFD), male with high-fat diet (M+HFD), female OVA-sensitized with high-fat diet (F+SHFD), and male OVA-sensitized with high-fat diet (M+SHFD). All rats were fed for 8 weeks with high-fat diet or standard pelts, and for another 4 weeks, they were sensitized with OVA or saline. At the end of the study, the tracheal responsiveness to methacholine, serum insulin, and blood glucose levels was measured. Also, insulin resistance indexes were determined. OVA-sensitization and diet-induced obesity caused the curve of methacholine concentration response to shifting to the left. In addition, results indicated that the EC50 (the effective concentration of methacholine generating 50% of peak response) in F+SHFD rats was statistically lower than M+SHFD group (p<0.05). Moreover, insulin resistance was higher in the F+SHFD than the M+SHFD group (p<0.001). These results suggest that insulin resistance and metabolic syndrome may be involved in the pathogenesis of obesity associated with OVA-sensitized rats condition, especially in female animals.


Assuntos
Asma/fisiopatologia , Broncoconstritores/farmacologia , Dieta Hiperlipídica , Resistência à Insulina , Cloreto de Metacolina/farmacologia , Obesidade/fisiopatologia , Traqueia/efeitos dos fármacos , Alérgenos , Animais , Glicemia/análise , Modelos Animais de Doenças , Feminino , Insulina/sangue , Masculino , Ovalbumina , Ratos Wistar , Traqueia/fisiopatologia
11.
Ann Allergy Asthma Immunol ; 122(5): 492-497, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831260

RESUMO

BACKGROUND: Recurrent wheezing in early life is transient in most children. The significance of airway hyperresponsiveness (AHR) in persistence of respiratory symptoms from infancy to early childhood is controversial. OBJECTIVE: We evaluated whether AHR in wheezy infants predicts doctor-diagnosed asthma (DDA) or AHR at the age of 6 years. METHODS: Sixty-one wheezy infants (age 6-24 months) were followed up to the median age of 6 years. Lung function and AHR with methacholine challenge test were assessed at infancy and 6 years. The exercise challenge test was performed at the age of 6 years. Atopy was assessed with skin prick tests. RESULTS: At 6 years, 21 (34%) of the children had DDA. Children with DDA had higher logarithmic transformed dose-response slope (LOGDRS) to methacholine in infancy than children without DDA (0.047 vs 0.025; P = .033). Furthermore, AHR to methacholine in infancy and at 6 years were associated with each other (r = 0.324, P = .011). Children with exercise-induced bronchoconstriction (EIB) at 6 years were more reactive to methacholine in infancy than those without EIB (P = .019). CONCLUSION: Increased AHR in symptomatic infants was associated with increased AHR, DDA, and EIB at median the age of 6 years, suggesting early establishment of AHR.


Assuntos
Asma Induzida por Exercício/diagnóstico , Asma/diagnóstico , Hipersensibilidade Respiratória/diagnóstico , Sons Respiratórios/fisiopatologia , Asma/fisiopatologia , Asma Induzida por Exercício/fisiopatologia , Testes de Provocação Brônquica , Broncoconstrição , Criança , Pré-Escolar , Teste de Esforço , Feminino , Seguimentos , Humanos , Lactente , Masculino , Cloreto de Metacolina/administração & dosagem , Estudos Prospectivos , Hipersensibilidade Respiratória/fisiopatologia , Testes Cutâneos
12.
Exerc Immunol Rev ; 25: 50-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785869

RESUMO

BACKGROUND: Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study evaluated the participation of SOCS-JAK-STAT signaling in the effects of AT on airway inflammation, remodeling and hyperresponsiveness in a model of allergic airway inflammation. METHODS: C57Bl/6 mice were divided into Control (Co), Exercise (Ex), HDM (HDM), and HDM+Exercise (HDM+ Ex). Dermatophagoides pteronyssinus (100ug/mouse) were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49. AT was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52. RESULTS: AT inhibited HDM-induced total cells (p<0.001), eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in BAL, and eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in peribronchial space. AT also reduced BAL levels of IL-4 (p<0.001), IL-5 (p<0.001), IL-13 (p<0.001), CXCL1 (p<0.01), IL-17 (p<0.01), IL-23 (p<0.05), IL-33 (p<0.05), while increased IL- 10 (p<0.05). Airway collagen fibers (p<0.01), elastic fibers p<0.01) and mucin (p<0.01) were also reduced by AT. AT also inhibited HDM-induced airway hyperresponsiveness (AHR) to methacholine 6,25mg/ml (p<0.01), 12,5mg/mL (p<0.01), 25mg/mL (p<0.01) and 50mg/mL (p<0.01). Mechanistically, AT reduced the expression of STAT6 (p<0.05), STAT3 (p<0.001), STAT5 (p<0.01) and JAK2 (p<0.001), similarly by peribronchial leukocytes and by airway epithelial cells. SOCS1 expression (p<0.001) was upregulated in leukocytes and in epithelial cells, SOCS2 (p<0.01) was upregulated in leukocytes and SOCS3 down-regulated in leukocytes (p<0.05) and in epithelial cells (p<0.001). CONCLUSIONS: AT reduces asthma phenotype involving SOCSJAK- STAT signaling.


Assuntos
Asma/metabolismo , Janus Quinases/metabolismo , Condicionamento Físico Animal , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Modelos Animais de Doenças , Eosinófilos/citologia , Interleucinas/metabolismo , Linfócitos/citologia , Cloreto de Metacolina , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Hipersensibilidade Respiratória/metabolismo
15.
Biofactors ; 45(1): 75-84, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30521085

RESUMO

The present study aimed to investigate the role of microRNA-146a and its adapter proteins [interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6)] in the pathogenesis of ovalbumin (OVA)-sensitized rats in association with the diet-induced obesity condition. Twenty male Wistar rats were divided into four groups: control with normal diet (ND), OVA-sensitized with normal diet (S + ND), high-fat diet (HFD), and OVA-sensitized with high-fat diet (S + HFD). All the animals were fed for 8 weeks with standard pelts or high-fat diet, and were then sensitized and challenged with OVA or saline for another 4 weeks. The tracheal responsiveness to methacholine, serum protein levels, and lipid profile levels was measured by the ELISA method. Moreover, the gene expression level of microRNA-146a (miR-146a) was measured in the lung tissue of the rats using the real-time PCR method. Maximum response to methacholin increased in the S + HFD group in compared with ND, S + ND, and HFD groups (P < 0.05 to P < 0.001). Moreover, in the S + HFD group the mRNA expression levels of miRNA-146a increased in the lung tissue (P < 0.001). In addition, the protein analysis results showed that IRAK1, TRAF6, NF-kB, and IL-1ß protein levels were high in the S + HFD group compared to the ND and HFD groups; however, in compared with the S + ND group, only the IL-1ß protein level was higher in the S + HFD group (P < 0.05). These results suggest that a defect in the NF-kB-miR-146a negative feedback loop may be involved in the pathogenesis of obesity associated with OVA-sensitized condition. © 2018 BioFactors, 45(1):75-84, 2019.


Assuntos
Alérgenos/administração & dosagem , Retroalimentação Fisiológica , MicroRNAs/genética , NF-kappa B/genética , Obesidade/genética , Ovalbumina/administração & dosagem , Alérgenos/imunologia , Animais , Testes de Provocação Brônquica , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Imunização , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Cloreto de Metacolina/administração & dosagem , Cloreto de Metacolina/imunologia , MicroRNAs/imunologia , NF-kappa B/imunologia , Obesidade/etiologia , Obesidade/imunologia , Obesidade/patologia , Ovalbumina/imunologia , Ratos , Ratos Wistar , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/imunologia
16.
Respir Physiol Neurobiol ; 259: 136-142, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217723

RESUMO

A certain amount of time is required to achieve a maximal contraction from airway smooth muscle (ASM) and stretches of substantial magnitude, such as the ones imparted by deep inspirations (DIs), interfere with contraction. The duration of ASM contraction without interference may thus affect its shortening, its mechanical response to DIs and the overall toll it exerts on the respiratory system. In this study, the effect of changing the interval between DIs on the dynamics of ASM was examined in vitro. Isolated bronchi derived from guinea pigs were held isotonically and stimulated to both contract and relax, in a randomized order, in response to 10-5 M of methacholine and 10-6 M of isoproterenol, respectively. Interference to ASM was inflicted after 2, 5, 10 and 30 min in a randomized order, by imposing a stretch that simulated a DI. The shortening before the stretch, the stiffness before and during the stretch, the post-stretch elongation of ASM and the ensuing re-shortening were measured. These experiments were also performed in the presence of simulated tidal breathing achieved through force fluctuations. The results demonstrate that, with or without force fluctuations, increasing the interval between simulated DIs increased shortening and post-stretch elongation, but not stiffness and re-shortening. These time-dependent effects were not observed when ASM was held in the relaxed state. These findings may help understand to which extent ASM shortening and the regulatory effect of DI are affected by changing the interval between DIs. The potential consequences of these findings on airway narrowing are also discussed.


Assuntos
Resistência das Vias Respiratórias/fisiologia , Brônquios/citologia , Inalação/fisiologia , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Dinâmica não Linear , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Feminino , Cobaias , Técnicas In Vitro , Inalação/efeitos dos fármacos , Isoproterenol/farmacologia , Cloreto de Metacolina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Estimulação Física , Fatores de Tempo
17.
Toxicol Appl Pharmacol ; 364: 153-163, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423287

RESUMO

Incorporation of multi-wall carbon nanotubes (MWCNT) into materials has raised concerns about their potential hazards to manufacturing workers. In animal models, airway inflammation and lung fibrosis follow aspiration, instillation, and inhalation exposures to MWCNT. However, the effects of MWCNT on pulmonary function, airway reactivity and airway epithelium function following inhalation exposure has not been studied. We investigated whether inhaled MWCNT affects lung resistance (RL) and dynamic compliance (Cdyn), reactivity to inhaled methacholine (MCh), epithelial regulation of airway reactivity to MCh in vitro, and airway epithelial ion transport. Male rats were exposed by whole body inhalation for 6 h to air or aerosolized MWCNT (0.5, 1 or 5 mg/m3) for one or nine days. Eighteen h after 1 d exposure to 5 mg/m3 MWCNT, basal RL was increased and basal Cdyn was decreased; changes did not persist for 7 d. Reactivity to MCh (RL) was increased and Cdyn responses were decreased at 18 h, but not 7 d after exposure to 1 and 5 mg/m3 MWCNT. The effects of i.t.-instilled MWCNT and nitrogen-doped MWCNT (N-MWCNT) on pulmonary function and reactivity to MCh at doses comparable to deposition after inhalation of 5 mg/m3 at 1 d and 0.5, 1, and 5 mg/m3 MWCNT 9 d-exposures were compared. Both nanoparticles increased airway reactivity (RL); N-MWCNT did not affect Cdyn responses. Lung function and airway reactivity are altered following a single MWCNT inhalation and generally subside over time. Given i.t., MWCNT's and N-MWCNT's effects were comparable, but N-MWCNT evoke smaller changes in Cdyn responses.


Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Broncoconstrição/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Nitrogênio/toxicidade , Aerossóis , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Testes de Provocação Brônquica , Broncoconstritores/administração & dosagem , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Exposição por Inalação , Transporte de Íons , Pulmão/metabolismo , Pulmão/fisiopatologia , Complacência Pulmonar/efeitos dos fármacos , Masculino , Cloreto de Metacolina/administração & dosagem , Nanotubos de Carbono/química , Nitrogênio/química , Permeabilidade , Ratos Sprague-Dawley , Medição de Risco , Fatores de Tempo
18.
Am J Respir Cell Mol Biol ; 60(4): 434-444, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30359078

RESUMO

Cystic fibrosis (CF) is an autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator gene. Many patients with CF have asthma-like symptoms and airway hyperresponsiveness, which are potentially associated with altered airway smooth muscle (ASM) contractility. Our goal in this study was to assess the contractility of the CF intrapulmonary ASM. ASM strips were dissected from human control and CF intrapulmonary airways, and assessed for methacholine-induced shortening velocity, maximal force, and stress. We also assessed isoproterenol responses in maximally methacholine-contracted ASM. ASM strips were then incubated for 16 hours with IL-13 and measurements were repeated. Myosin light chain kinase (MLCK) expression was assessed by Western blotting. Airways were immunostained for morphometry. ASM mass was increased in CF airways, which likely contributes to airway hyperresponsiveness. Although ASM contractile properties were not intrinsically different between patients with CF and control subjects, CF ASM responded differently in the presence of the inflammatory mediator IL-13, showing impairment in ß-adrenergic-induced relaxation. Indeed, the percentage of relaxation measured at maximal isoproterenol concentrations in the CF ASM was significantly lower after incubation with IL-13 (46.0% ± 6.7% relaxation) than without IL-13 (74.0% ± 7.7% relaxation, P = 0.018). It was also significantly lower than that observed in control ASM incubated with IL-13 (68.8% ± 4.9% relaxation, P = 0.048) and without IL-13 (82.4% ± 9.9%, P = 0.0035). CF ASM incubated with IL-13 also expressed greater levels of MLCK. Thus, our data suggest that the combination of an increase in ASM mass, increased MLCK expression, and inflammation-induced ß-adrenergic hyporesponsiveness may contribute to airway dysfunction in CF.


Assuntos
Asma/patologia , Fibrose Cística/patologia , Contração Muscular/fisiologia , Músculo Liso/patologia , Hipersensibilidade Respiratória/patologia , Adulto , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Interleucina-13/farmacologia , Isoproterenol/farmacologia , Masculino , Cloreto de Metacolina/farmacologia , Pessoa de Meia-Idade , Quinase de Cadeia Leve de Miosina/biossíntese , Sistema Respiratório/patologia , Adulto Jovem
19.
Respir Physiol Neurobiol ; 259: 156-161, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30367990

RESUMO

To clarify the potential of dopamine to alter airway tone in the presence of different bronchoconstrictor stimuli, changes in airway function following dopamine administrations were characterized when the bronchial tone was elevated by stimulating the histaminic or cholinergic pathway. Airway resistance, tissue damping and tissue elastance were measured in anesthetized mechanically ventilated rabbits under baseline conditions, during steady-state bronchoconstriction induced by methacholine or histamine, and following intravenous dopamine (5 and 15 µg/kg/min). Bronchoconstriction induced by methacholine and histamine was significantly ameliorated by dopamine (14.8 ± 2.9% and 14.9 ± 2.9%; p < 0.05 for both), with no difference between the mode of stimuli. Dopamine had no effect on the tissue mechanics. These findings indicate that dopamine relaxes the elevated airway smooth muscle tone without affecting the lung periphery, and this effect is independent of the mode of constrictor stimuli. This profile of dopamine suggests its ability to treat effectively cholinergic and histaminergic bronchoconstriction, besides its positive inotropic effects on the myocardial contractility.


Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Dopamina/farmacologia , Histamina/farmacologia , Cloreto de Metacolina/farmacologia , Mecânica Respiratória/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Músculo Liso/efeitos dos fármacos , Coelhos
20.
J Asthma ; 56(1): 53-60, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29432042

RESUMO

OBJECTIVE: The "united airway disease" concept is based on the bidirectional interaction between asthma and rhinitis. The aim of this study was to determine the relationship between upper airway diseases and bronchial hyperresponsiveness (BHR), as well as their association with the fractional concentration of exhaled nitric oxide (FeNO) and atopy in patients with persistent symptoms suggestive of asthma requiring methacholine challenge testing (MCT) to confirm asthma diagnosis. METHODS: A cross-sectional prospective study was carried out in adult patients with persistent asthma-like symptoms and negative bronchodilator testing. FeNO and MCT were performed in all patients. Asthma was confirmed based on the presence of suggestive symptoms and MCT results. Associated upper airway diseases included allergic rhinitis, nonallergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). RESULTS: The study included 575 patients; asthma was confirmed in 32.3%, and FeNO values ≥ 50 ppb were found in 27% of the patients. Elevated FeNO was significantly associated to AERD. The prevalence of atopy in asthma patients was 86.6%. Atopy was present in 90.4% of patients with asthma and FeNO levels ≥ 50 ppb. A significant association was found between AERD, asthma, and FeNO ≥ 50 ppb. CONCLUSIONS: Patients with symptoms suggestive of asthma but negative bronchodilator testing are commonly seen in usual practice. In this population, the association of high FeNO levels and BHR to atopy, as well as to AERD, suggests the presence eosinophilic inflammation in both the upper and lower airways and supports the "one airway" hypothesis.


Assuntos
Asma/epidemiologia , Hiper-Reatividade Brônquica/epidemiologia , Hipersensibilidade/epidemiologia , Pólipos Nasais/epidemiologia , Óxido Nítrico/análise , Rinite/epidemiologia , Adulto , Asma Induzida por Aspirina/epidemiologia , Testes de Provocação Brônquica , Estudos Transversais , Feminino , Humanos , Masculino , Cloreto de Metacolina/farmacologia , Pessoa de Meia-Idade , Estudos Prospectivos , Fumar/epidemiologia , Espirometria
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