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1.
Bull Exp Biol Med ; 173(4): 486-489, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36058975

RESUMO

We studied contractile responses of isolated airway smooth muscle segments from rats with metabolic syndrome. Metabolic syndrome was induced in rats by high-fat and high-carbohydrate diet. It was shown that metabolic syndrome was associated with an increase of bronchoconstrictor action of cholinergic receptor activator carbacholine (0.1-100 µM) and a decrease of the dilatory effect of ß2-adrenoreceptor activator salbutamol (0.1-100 µM). The observed effects of agonists are epithelium-dependent. Disorders in contractile activity in the airway smooth muscles were accompanied by bronchial epithelium destruction, immune inflammation in the bronchial wall, muscular and peribronchial adipose tissue hypertrophy.


Assuntos
Broncoconstritores , Síndrome Metabólica , Albuterol/farmacologia , Animais , Brônquios , Broncoconstritores/metabolismo , Broncoconstritores/farmacologia , Carbacol/metabolismo , Carbacol/farmacologia , Carboidratos/farmacologia , Síndrome Metabólica/metabolismo , Contração Muscular , Músculo Liso , Ratos , Receptores Colinérgicos/metabolismo
2.
J Appl Physiol (1985) ; 132(5): 1137-1144, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35358399

RESUMO

Inhaling carbon dioxide (CO2) in humans is known to cause inconsistent effects on airway function. These could be due to direct effects of CO2 on airway smooth muscle or to changes in minute ventilation (V̇e). To address this issue, we examined the responses of the respiratory system to inhaled methacholine in healthy subjects and subjects with mild asthma while breathing air or gas mixtures containing 2% or 4% CO2. Respiratory mechanics were measured by a forced oscillation technique at 5 Hz during tidal breathing. At baseline, respiratory resistance (R5) was significantly higher in subjects with asthma (2.53 ± 0.38 cmH2O·L-1·s) than healthy subjects (2.11 ± 0.42 cmH2O·L-1·s) (P = 0.008) with room air. Similar values were observed with CO2 2% or 4% in the two groups. V̇e, tidal volume (VT), and breathing frequency (BF) significantly increased with CO2-containing mixtures (P < 0.001) with insignificant differences between groups. After methacholine, the increase in R5 and the decrease in respiratory reactance (X5) were significantly attenuated up to about 50% with CO2-containing mixtures instead of room air in both asthmatic (P < 0.001) and controls (P < 0.001). Mediation analysis showed that the attenuation of methacholine-induced changes in respiratory mechanics by CO2 was due to the increase in V̇e (P = 0.006 for R5 and P = 0.014 for X5) independently of the increase in VT or BF, rather than a direct effect of CO2. These findings suggest that the increased stretching of airway smooth muscle by the CO2-induced increase in V̇e is a mechanism through which hypercapnia can attenuate bronchoconstrictor responses in healthy subjects and subjects with mild asthma.NEW & NOTEWORTHY The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2 significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2 was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.


Assuntos
Asma , Broncoconstrição , Resistência das Vias Respiratórias/fisiologia , Broncoconstritores/farmacologia , Dióxido de Carbono/farmacologia , Humanos , Hipercapnia , Hiperventilação , Cloreto de Metacolina/farmacologia
3.
Am J Physiol Lung Cell Mol Physiol ; 321(6): L1105-L1118, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34668415

RESUMO

Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce insulin resistance, can reduce circulating insulin, thereby preventing airway hyperreactivity in rats with dietary obesity. Male and female rats were fed a high- or low-fat diet for 5 wk. Some male rats were simultaneously treated with metformin (100 mg/kg orally). In separate experiments, after 5 wk of a high-fat diet, some rats were switched to a low-fat diet, whereas others continued a high-fat diet for an additional 5 wk. Bronchoconstriction and bradycardia in response to bilateral electrical vagus nerve stimulation or to inhaled methacholine were measured in anesthetized and vagotomized rats. Body weight, body fat, caloric intake, fasting glucose, and insulin were measured. Vagally induced bronchoconstriction was potentiated only in male rats on a high-fat diet. Males gained more body weight, body fat, and had increased levels of fasting insulin compared with females. Metformin prevented development of vagally induced airway hyperreactivity in male rats on high-fat diet, in addition to inhibiting weight gain, fat gain, and increased insulin. In contrast, switching rats to a low-fat diet for 5 wk reduced body weight and body fat, but it did not reverse fasting glucose, fasting insulin, or potentiation of vagally induced airway hyperreactivity. These data suggest that medications that target insulin may be effective treatment for obesity-related asthma.


Assuntos
Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/tratamento farmacológico , Broncoconstrição , Dieta Hiperlipídica/efeitos adversos , Hiperinsulinismo/prevenção & controle , Metformina/farmacologia , Obesidade/complicações , Animais , Asma/induzido quimicamente , Asma/metabolismo , Asma/patologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Broncoconstritores/toxicidade , Feminino , Glucose/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Hipoglicemiantes/farmacologia , Masculino , Cloreto de Metacolina/toxicidade , Ratos , Ratos Sprague-Dawley , Nervo Vago/efeitos dos fármacos , Aumento de Peso
4.
Biosens Bioelectron ; 190: 113439, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166943

RESUMO

The methacholine challenge test is considered to be the gold standard bronchoprovocation test used to diagnose asthma, and this test is always performed in pulmonary function labs or doctors' offices. Methacholine (MCH) acts by inducing airway tightening/bronchoconstriction, and more importantly, MCH is hydrolyzed by cholinesterase enzyme (ChE). Recently, the American Thoracic Society raised concerns about pulmonary function testing during the COVID-19 pandemic due to recently reported correlation between cholinesterase and COVID-19 pneumonia severity/mortality, and it was shown that cholinesterase levels are reduced in the acute phase of severe COVID-19 pneumonia. This work describes the microfabrication of potentiometric sensors using copper as the substrate and chemically polymerized graphene nanocomposites as the transducing layer for tracking the kinetics of MCH enzymatic degradation in real blood samples. The in-vitro estimation of the characteristic parameters of the MCH metabolism [Michaelis-Menten constant (Km) and reaction velocity (Vmax)] were found to be 241.041 µM and 56.8 µM/min, respectively. The proposed sensor is designed to be used as a companion diagnostic device that can (i) answer questions about patient eligibility to perform methacholine challenge tests, (ii) individualize/personalize medical dosing of methacholine, (iii) provide portable and inexpensive devices allowing automated readouts without the need for operator intervention (iv) recommend therapeutic interventions including intensive care during early stages and reflecting the disease state of COVID-19 pneumonia. We hope that this methacholine electrochemical sensor will help in assaying ChE activity in a "timely" manner and predict the severity and prognosis of COVID-19 to improve treatment outcomes and decrease mortality.


Assuntos
Técnicas Biossensoriais , COVID-19 , Broncoconstritores , Humanos , Cloreto de Metacolina , Pandemias , SARS-CoV-2
5.
Respir Physiol Neurobiol ; 292: 103705, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34062282

RESUMO

Balb/c mice respiratory mechanics was studied in two intravenous methacholine (MCh) protocols: bolus and continuous infusion. The Constant Phase Model (CPM) was used in this study. The harmonic distortion index (kd) was used to assess the respiratory system nonlinearity. The analysis of variance showed difference between groups (OVA vs control) and among doses for both protocols. Bolus protocol posttest: there was a difference between OVA and control at 0.3 and 1 mg/kg doses (p<0.0001 and p<0.001) for Rn. Infusion: there was a difference between OVA and control at 192 µg.kg-1.min-1 dose for Rn, G and H, (p<0.01; p<0.001; p<0.001). An increment was found in kd values near to the observed peak values in bolus protocol. The bolus protocol could better differentiate inflamed and non-inflamed airway resistance, whereas the differences between OVA and control in continuous infusion protocol were associated to airway- and, mainly, parenchyma-related parameters. Moreover, the bolus protocol presented a higher nonlinear degree compared to the infusion protocol.


Assuntos
Asma/induzido quimicamente , Broncoconstritores/administração & dosagem , Cloreto de Metacolina/administração & dosagem , Modelos Teóricos , Mecânica Respiratória/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C
6.
J Korean Med Sci ; 36(19): e130, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34002550

RESUMO

BACKGROUND: Most epidemiological studies depend on the subjects' response to asthma symptom questionnaires. Questionnaire-based study for childhood asthma prevalence may overestimate the true prevalence. The aim of this study was to investigate the prevalence of "Current asthma" using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and methacholine challenge test in Korean children. METHODS: Our survey on allergic disease included 4,791 children (age 7-12 years) from 2010 to 2014 in Korean elementary schools. Bronchial hyperresponsiveness (BHR) was defined as provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20) ≤ 16 mg/mL. "Current asthma symptoms" was defined as positive response to "Wheezing, current," "Treatment, current," or "Exercise, current." "Current asthma" was defined when the subjects with "Current asthma symptoms" showed BHR on the methacholine challenge test or had less than 70% of predicted FEV1 value. RESULTS: The prevalence of "Wheezing, ever," "Wheezing, current," "Diagnosis, ever," "Treatment, current," "Exercise, current," and "Current asthma symptoms" was 19.6%, 6.9%, 10.0%, 3.3%, 3.5%, and 9.6%, respectively, in our cross-sectional study of Korean elementary school students. The prevalence of BHR in elementary school students was 14.5%. The prevalence of BHR in children with "Wheezing, ever," "Wheezing, current," "Diagnosis, ever," "Treatment, current," and "Exercise, current" was 22.3%, 30.5%, 22.4%, 28.8%, and 29.9%, respectively. BHR was 26.1% in those with "Current asthma symptoms." The prevalence of "Current asthma" was 2.7%. CONCLUSIONS: Our large-scale study provides 2.7% prevalence of current asthma in Korean elementary school children. Since approximately one third of the children who have "Current asthma symptoms" present BHR, both subjective and objective methods are required to accurately predict asthma in subjects with asthma symptoms.


Assuntos
Asma/epidemiologia , Hiper-Reatividade Brônquica/epidemiologia , Testes de Provocação Brônquica/métodos , Broncoconstritores/administração & dosagem , Cloreto de Metacolina/administração & dosagem , Asma/diagnóstico , Hiper-Reatividade Brônquica/diagnóstico , Testes de Provocação Brônquica/efeitos adversos , Broncoconstritores/efeitos adversos , Criança , Estudos Transversais , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Cloreto de Metacolina/efeitos adversos , Prevalência , República da Coreia/epidemiologia , Sons Respiratórios/etiologia , Inquéritos e Questionários
7.
BMC Pulm Med ; 21(1): 153, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957916

RESUMO

BACKGROUND: Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma. METHODS: Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle ß, FEV1, FVC, FEV1/FVC, FEF50%, FEF25-75%) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified. RESULTS: A total of 2983 tests were analyzed in adults aged 18-40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p < 0.001). FEF50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF50% ≥ 110% as a cutoff level. CONCLUSIONS: This study highlights the role of FEF50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.


Assuntos
Asma/diagnóstico , Hiper-Reatividade Brônquica/diagnóstico , Testes de Provocação Brônquica , Broncoconstritores/administração & dosagem , Cloreto de Metacolina/administração & dosagem , Espirometria , Adulto , Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Estudos Transversais , Feminino , Volume Expiratório Forçado , Humanos , Israel , Modelos Logísticos , Masculino , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Capacidade Vital , Adulto Jovem
8.
Exp Biol Med (Maywood) ; 246(9): 1094-1103, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33601911

RESUMO

Assessment of respiratory mechanics extends from basic research and animal modeling to clinical applications in humans. However, to employ the applications in human models, it is desirable and sometimes mandatory to study non-human animals first. To acquire further precise and controlled signals and parameters, the animals studied must be further distant from their spontaneous ventilation. The majority of respiratory mechanics studies use positive pressure ventilation to model the respiratory system. In this scenario, a few drug categories become relevant: anesthetics, muscle blockers, bronchoconstrictors, and bronchodilators. Hence, the main objective of this study is to briefly review and discuss each drug category, and the impact of a drug on the assessment of respiratory mechanics. Before and during the positive pressure ventilation, the experimental animal must be appropriately sedated and anesthetized. The sedation will lower the pain and distress of the studied animal and the plane of anesthesia will prevent the pain. With those drugs, a more controlled procedure is carried out; further, because many anesthetics depress the respiratory system activity, a minimum interference of the animal's respiration efforts are achieved. The latter phenomenon is related to muscle blockers, which aim to minimize respiratory artifacts that may interfere with forced oscillation techniques. Generally, the respiratory mechanics are studied under appropriate anesthesia and muscle blockage. The application of bronchoconstrictors is prevalent in respiratory mechanics studies. To verify the differences among studied groups, it is often necessary to challenge the respiratory system, for example, by pharmacologically inducing bronchoconstriction. However, the selected bronchoconstrictor, doses, and administration can affect the evaluation of respiratory mechanics. Although not prevalent, studies have applied bronchodilators to return (airway resistance) to the basal state after bronchoconstriction. The drug categories can influence the mathematical modeling of the respiratory system, systemic conditions, and respiratory mechanics outcomes.


Assuntos
Modelos Animais , Mecânica Respiratória/efeitos dos fármacos , Anestésicos/farmacologia , Animais , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Bloqueadores Neuromusculares/farmacologia
9.
BMC Pulm Med ; 21(1): 49, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536015

RESUMO

BACKGROUND: Cough variant asthma (CVA) is one of the special populations of asthma. The aim of the study was to compare small airways, the degree of bronchial hyperresponsiveness (BHR) and airway inflammatory subtypes between CVA and classic asthma (CA), and investigate the relationship between these markers to determine the accuracy as indicators of CVA. METHODS: A total of 825 asthmatic patients participated in the study and 614 were included. 614 patients underwent spirometry and a bronchial challenge with methacholine and 459 patients performed induction sputum cell test. RESULTS: The number of CVA patients showed less small airway dysfunction than those of CA patients (p < 0.005). The degree of small airways dysfunction was higher in the CA group compared with the CVA group (p < 0.001). Small airways dysfunction was severer in the eosinophilic airway inflammatory subtype compared with other subtypes (p < 0.05).The area under curve of MMEF, FEF50 and FEF75 (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD20 and 4.7% of sputum eosinophils was the best diagnostic value for CVA with an AUC of 0.582 and 0.575 (p = 0.001 and p = 0.005, respectively). CONCLUSIONS: The eosinophilic airway inflammatory subtype may be increased small airway dysfunction. The value of small airways, BHR and induction sputum cells in CVA prediction, which reflected significant, but not enough to be clinically useful.


Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Proteína Catiônica de Eosinófilo/imunologia , Eosinófilos/imunologia , Escarro/imunologia , Adulto , Asma/complicações , Hiper-Reatividade Brônquica/induzido quimicamente , Testes de Provocação Brônquica , Broncoconstritores/administração & dosagem , Broncoconstritores/efeitos adversos , Tosse/imunologia , Relação Dose-Resposta a Droga , Proteína Catiônica de Eosinófilo/análise , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Contagem de Leucócitos , Masculino , Cloreto de Metacolina/administração & dosagem , Cloreto de Metacolina/efeitos adversos , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
10.
J Asthma ; 58(1): 69-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526153

RESUMO

OBJECTIVE: Interpretation of methacholine challenge testing (MCT) results depends on the patient's pretest probability of asthma as well as the provocative concentration (PC20); however, ordering providers rarely understand the complexity associated with its interpretation. This study investigated the clinical utility and efficiency of MCT at a tertiary center in evaluating pediatric asthma. METHODS: Retrospective chart review was done for all MCT done at a tertiary center over a six year period (2011-2017). Demographics, referring provider, referral diagnosis, current symptoms with and without exercise, and baseline spirometry were collected. Pretest probability of asthma was assigned by author (RB) who was blinded to MCT results and PC20. Post-test probability of asthma was assigned based on pretest probability, MCT result (+/-), and PC20. Three assigned asthma probability categories were "unlikely" "likely", and "very likely". RESULTS: Of 172 subjects (91 Females, age range 5-21 years), 64.9% of MCT results (n = 111)) were negative and 35.1% (n = 60)) were positive. One was inconclusive. Those who tested positive were shorter, lighter, younger and had lower forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio than those who tested negative (p < 0.05). Subjects with exercise symptoms only were less likely to test positive (OR 0.2, CI 0.1-0.5). In a majority of subjects (91.8%; 157/171), MCT increased the certainty of presence or absence of asthma. CONCLUSIONS: In our subject population, MCT could be useful in evaluating pediatric asthma if subject's pretest probability of asthma and PC20 was taken into account. It was not as useful for subjects with exercise symptoms only.


Assuntos
Asma/diagnóstico , Testes de Provocação Brônquica/métodos , Broncoconstritores/administração & dosagem , Cloreto de Metacolina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
11.
J Asthma ; 58(5): 625-632, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-31922916

RESUMO

Objective: This study aimed to evaluate the diagnostic value of the modified hypertonic saline bronchial provocation test (HS-BPT) for children with asthma by using the high-power Aerosol Provocation System (APS).Methods: A total of 330 children suspected of having asthma and receiving HS-BPT-APS were included in this prospective survey conducted in Guangzhou, China from February 2017 to September 2018. The positive rate of HS-BPT-APS and the volume and types of adverse reactions were observed. There was also a retrospective cohort of 123 children with suspected asthma who underwent a methacholine BPT from 2015 to 2017. Using the method of nearest neighbor matching, a comparison was made of the positive rate and adverse reaction between the methacholine BPT group and HS-BPT-APS group.Results: The total positive rate of HS-BPT-APS was 43.9%. Common adverse reactions included cough, wheezing and chest tightness. There were no serious adverse reactions. Results of nearest neighbor matching showed a difference in the positive rate between the methacholine BPT group and HS-BPT-APS group (8.1% vs 18.2%, p = 0.026), but there was no statistically significant difference between the age groups in patients who received the methacholine BPT or HS-BPT-APS. There was a similar adverse reaction rate in the two groups (p = 0.609).Conclusions: HS-BPT-APS is simple, safe, and time-saving, with few adverse reactions. The positive rate of HS-BPT-APS was higher than that of methacholine BPT in children with asthma. HS-BPT-APS may be a valuable tool in the diagnosis of children with asthma, and further study is required.


Assuntos
Asma/diagnóstico , Testes de Provocação Brônquica/métodos , Solução Salina Hipertônica/administração & dosagem , Aerossóis , Asma/fisiopatologia , Broncoconstritores/administração & dosagem , Criança , Pré-Escolar , Tosse , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Cloreto de Metacolina/administração & dosagem , Sons Respiratórios , Solução Salina Hipertônica/efeitos adversos
12.
Respir Physiol Neurobiol ; 282: 103545, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32927098

RESUMO

BACKGROUND: Oxygen therapy and mechanical ventilation are important predisposing factors for the development of bronchopulmonary dysplasia (BPD), leading to increased morbidity and mortality in premature infants. Oxygen toxicity mediated by reactive oxygen species (ROS) may play an important part in the development of BPD. We studied the effects of MnTBAP, a catalytic antioxidant on airway responsiveness and alveolar simplification in adult mice following neonatal hyperoxia. METHODS: Mice litters were randomized to 85 %O2 or room air (RA) on D3 for 12 days to receive either MnTBAP (10 mg/kg/d) or saline intraperitoneally. Methacholine challenge (MCC) performed at 8 and 12 weeks of age by whole-body plethysmography to assess airway reactivity. Alveolarization quantified on lung sections by radial alveolar count (RAC) and mean linear intercept (MLI). Cell counts assessed from bronchoalveolar lavage (BAL) performed at 15 weeks. RESULTS: Mice exposed to hyperoxia and MnTBAP (OXMN) had significantly higher airway reactivity post-MCC at 8 weeks compared to RA and O2 groups. At 12 weeks, airway reactivity was higher post-MCC in both hyperoxia and OXMN groups. MnTBAP did not attenuate hyperoxia-induced airway reactivity in adult mice. Hyperoxia exposed mice demonstrated large and distended alveoli on histopathology at 2 and 15 weeks. MnTBAP did not ameliorate hyperoxia-induced lung injury as assessed by RAC/MLI. Absolute lymphocyte count was significantly higher in BAL in the hyperoxia and OXMN groups. CONCLUSIONS: MnTBAP, a catalytic antioxidant, did not afford protection from hyperoxia-induced lung injury in adult mice.


Assuntos
Antioxidantes/farmacologia , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/prevenção & controle , Hiperóxia/complicações , Metaloporfirinas/farmacologia , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Broncoconstritores/administração & dosagem , Modelos Animais de Doenças , Feminino , Masculino , Metaloporfirinas/administração & dosagem , Cloreto de Metacolina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Pletismografia Total , Gravidez
13.
Rev Mal Respir ; 37(6): 462-473, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32487422

RESUMO

INTRODUCTION: A significant portion of symptoms in some lung diseases results from an excessive constriction of airways due to the contraction of smooth muscle and bronchial hyperresponsiveness. A better understanding of the extracellular molecules that control smooth muscle contractility is necessary to identify the underlying causes of the problem. STATE OF KNOWLEDGE: Almost a hundred molecules, some of which newly identified, influence the contractility of airway smooth muscle. While some molecules activate the contraction, others activate the relaxation, thus acting directly as bronchoconstrictors and bronchodilators, respectively. Other molecules do not affect contraction directly but rather influence it indirectly by modifying the effect of bronchoconstrictors and bronchodilators. These are called bronchomodulators. Some of these bronchomodulators increase the contractile effect of bronchoconstrictors and could thus contribute to bronchial hyperresponsiveness. PROSPECTS: Considering the high number of molecules potentially involved, as well as the level of functional overlap between some of them, identifying the extracellular molecules responsible for excessive airway constriction in a patient is a major contemporary challenge.


Assuntos
Hiper-Reatividade Brônquica/etiologia , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Animais , Asma/etiologia , Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/fisiologia , Broncoconstritores/metabolismo , Broncodilatadores/metabolismo , Espaço Extracelular/metabolismo , Humanos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Sistema Respiratório/fisiopatologia
15.
Exp Biol Med (Maywood) ; 245(8): 680-689, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32183551

RESUMO

IMPACT STATEMENT: Respiratory mechanics studies are associated with fundamental research and translational studies; the present work thus investigates this particular matter. Our current research describes differences and similarities between two different ways of administrating a very prevalent bronchoconstrictor (methacholine) in an aging process scenario. The core issue of our work is related with troubles we find with the bolus protocol and the application of the mathematical model used to assess the respiratory mechanics. Our findings reveal the continuous infusion as an alternative to these problems and we hope to provide the proper foundations to a more reliable assessment in the respiratory field.


Assuntos
Broncoconstritores/farmacologia , Cloreto de Metacolina/farmacologia , Mecânica Respiratória , Animais , Broncoconstritores/administração & dosagem , Infusões Intravenosas/métodos , Infusões Intravenosas/normas , Cloreto de Metacolina/administração & dosagem , Camundongos , Modelos Teóricos , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/crescimento & desenvolvimento
16.
Sci Rep ; 10(1): 1962, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029879

RESUMO

Mechanisms mediating the protective effects of molecular hydrogen (H2) are not well understood. This study explored the possibility that H2 exerts its anti-inflammatory effect by modulating energy metabolic pathway switch. Activities of glycolytic and mitochondrial oxidative phosphorylation systems were assessed in asthmatic patients and in mouse model of allergic airway inflammation. The effects of hydrogen treatment on airway inflammation and on changes in activities of these two pathways were evaluated. Monocytes from asthmatic patients and lungs from ovalbumin-sensitized and challenged mice had increased lactate production and glycolytic enzyme activities (enhanced glycolysis), accompanied by decreased ATP production and mitochondrial respiratory chain complex I and III activities (suppressed mitochondrial oxidative phosphorylation), indicating an energy metabolic pathway switch. Treatment of ovalbumin-sensitized and challenged mice with hydrogen reversed the energy metabolic pathway switch, and mitigated airway inflammation. Hydrogen abrogated ovalbumin sensitization and challenge-induced upregulation of glycolytic enzymes and hypoxia-inducible factor-1α, and downregulation of mitochondrial respiratory chain complexes and peroxisome proliferator activated receptor-γ coactivator-1α. Hydrogen abrogated ovalbumin sensitization and challenge-induced sirtuins 1, 3, 5 and 6 downregulation. Our data demonstrates that allergic airway inflammation is associated with an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis. Hydrogen inhibits airway inflammation by reversing this switch. Hydrogen regulates energy metabolic reprogramming by acting at multiple levels in the energy metabolism regulation pathways.


Assuntos
Asma/tratamento farmacológico , Glicólise/efeitos dos fármacos , Hidrogênio/administração & dosagem , Leucócitos Mononucleares/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Asma/sangue , Asma/induzido quimicamente , Asma/imunologia , Broncoconstritores/efeitos adversos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glicólise/imunologia , Humanos , Ácido Láctico/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Cloreto de Metacolina/efeitos adversos , Camundongos , Pessoa de Meia-Idade , Ovalbumina/imunologia , Cultura Primária de Células
17.
J Asthma ; 57(1): 11-20, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30634874

RESUMO

Objective: New treatments are needed for cases of asthma that are refractory to traditional therapies. In this study, we examined the effect of oral nintedanib, an intracellular inhibitor of tyrosine kinases, on airway hyper-responsiveness (AHR) and airway smooth muscle cells, using a mouse model of experimental asthma. Methods: Asthma was experimentally induced in mice via subcutaneous injection of ovalbumin (OVA). A group of saline-injected mice served as a control group. The OVA mice were then divided into four treatment groups according to the dose of nintedanib. AHR was examined via exposure to vaporized methacholine. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cell counts and Th2 cytokine concentrations. Results: Baseline levels of AHR and airway inflammation were higher in OVA mice than in the control group. Treatment with nintedanib lowered AHR, BALF cell counts and BALF cytokine levels in a dose-dependent fashion. The effect of nintedanib was comparable to that of dexamethasone. In particular, treatment with nintedanib lowered the expression of transforming growth factor-ß1 and inhibited the expression and phosphorylation of platelet-derived growth factor receptor-ß, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, fibroblast growth factor receptor 2 (FGFR2), FGFR3, and extracellular signal-regulated kinase. Conclusions: Nintedanib lowered AHR and the expression of factors associated with airway inflammation and remodeling in a mouse model of experimental asthma. Our results suggest that nintedanib may be useful in the treatment of asthma.


Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Brônquios/efeitos dos fármacos , Indóis/administração & dosagem , Mediadores da Inflamação/metabolismo , Doença Aguda/terapia , Administração por Inalação , Administração Oral , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/imunologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/imunologia , Animais , Asma/diagnóstico , Asma/imunologia , Brônquios/imunologia , Brônquios/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Broncoconstritores/administração & dosagem , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Mediadores da Inflamação/análise , Cloreto de Metacolina/administração & dosagem , Camundongos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia
18.
Respir Physiol Neurobiol ; 274: 103358, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31811939

RESUMO

Mammals airways are extensively innervated by the vagus nerve, which controls the airway diameter and bronchial tone. However, very few studies described the respiratory function and lung morphology after vagal section. In the present study, we evaluated the respiratory mechanics after aerosolization of vehicle (to obtain control values), a muscarinic agonist (methacholine), a ß2-adrenergic agonist (salbutamol) or a muscarinic antagonist (ipratropium bromide) in intact (Vi) and bilaterally vagotomized (Vx) Swiss male mice. Different group was established for morphometric analyze. The total lung resistance, airway resistance, elastance, compliance, lung tissue damping, lung tissue elastance, and morphological parameters (collagen and elastic fibers) were significantly different in the Vx group compared to the Vi group. Bronchoconstrictor and bronchodilators change the respiratory function of the Vx group. In conclusion, the vagus nerve modulates the lung function in response to bronchoconstriction and bronchodilation, as well as lung architecture of mice.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Antagonistas Muscarínicos/farmacologia , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia , Vagotomia , Nervo Vago/fisiologia , Albuterol/farmacologia , Animais , Colágeno , Tecido Elástico , Ipratrópio/farmacologia , Pulmão/ultraestrutura , Masculino , Cloreto de Metacolina/farmacologia , Camundongos , Agonistas Muscarínicos/farmacologia
19.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L264-L275, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31800261

RESUMO

Duodenogastroesophageal reflux (DGER) is associated with chronic lung disease. Bile acids (BAs) are established markers of DGER aspiration and are important risk factors for reduced post-transplant lung allograft survival by disrupting the organ-specific innate immunity, facilitating airway infection and allograft failure. However, it is unknown whether BAs also affect airway reactivity. We investigated the acute effects of 13 BAs detected in post-lung-transplant surveillance bronchial washings (BW) on airway contraction. We exposed precision-cut slices from human and mouse lungs to BAs and monitored dynamic changes in the cross-sectional luminal area of peripheral airways using video phase-contrast microscopy. We also used guinea pig tracheal rings in organ baths to study BA effects in proximal airway contraction induced by electrical field stimulation. We found that most secondary BAs at low micromolar concentrations strongly and reversibly relaxed smooth muscle and inhibited peripheral airway constriction induced by acetylcholine but not by noncholinergic bronchoconstrictors. Similarly, secondary BAs strongly inhibited cholinergic constrictions in tracheal rings. In contrast, TC-G 1005, a specific agonist of the BA receptor Takeda G protein-coupled receptor 5 (TGR5), did not cause airway relaxation, and Tgr5 deletion in knockout mice did not affect BA-induced relaxation, suggesting that this receptor is not involved. BAs inhibited acetylcholine-induced inositol phosphate synthesis in human airway smooth muscle cells overexpressing the muscarinic M3 receptor. Our results demonstrate that select BAs found in BW of patients with lung transplantation can affect airway reactivity by inhibiting the cholinergic contractile responses of the proximal and peripheral airways, possibly by acting as antagonists of M3 muscarinic receptors.


Assuntos
Acetilcolina/metabolismo , Ácidos e Sais Biliares/farmacologia , Broncoconstrição/efeitos dos fármacos , Pulmão/fisiopatologia , Animais , Broncoconstritores/farmacologia , Ácido Quenodesoxicólico/farmacologia , Estimulação Elétrica , Cobaias , Humanos , Fosfatos de Inositol/biossíntese , Pulmão/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Muscarínicos/metabolismo , Serotonina/farmacologia , Ácido Taurolitocólico/farmacologia , Traqueia/efeitos dos fármacos
20.
Respir Physiol Neurobiol ; 274: 103355, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31805396

RESUMO

Nocturnal worsening of asthma may be due to reduced lung volumes and fewer sigh breaths, which have been shown to increase airway resistance and bronchoreactivity. We hypothesized that mimicking deep inspiration using nocturnal mechanical support would improve symptoms in patients with asthma. Subjects with asthma underwent usual care and bilevel positive airway pressure (PAP) therapy for 4 weeks, separated by 4 weeks, and methacholine challenge (PC20) and subjective assessments. 13 patients with asthma alone and 8 with asthma + OSA completed the protocol. Change in bronchoreactivity (ratio of Post/Pre PC20) was not significantly different during usual care and bilevel PAP [0.86 (IQR 0.19, 1.82) vs 0.94 (IQR 0.56, 2.5), p = 0.88], nor was the change in Asthma Control Test different: 0.1 ±â€¯2.2 vs. -0.2 ±â€¯2.9, p = 0.79, respectively. Bilevel PAP therapy for four weeks did not improve subjective or objective measures of asthma severity in patients with asthma or those with asthma and OSA, although there was heterogeneity in response.


Assuntos
Asma/terapia , Testes de Provocação Brônquica , Pressão Positiva Contínua nas Vias Aéreas , Avaliação de Resultados em Cuidados de Saúde , Apneia Obstrutiva do Sono/terapia , Adulto , Asma/complicações , Broncoconstritores , Estudos Cross-Over , Feminino , Humanos , Medidas de Volume Pulmonar , Masculino , Cloreto de Metacolina/administração & dosagem , Pessoa de Meia-Idade , Apneia Obstrutiva do Sono/etiologia
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