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Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways.
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Bradicinina , Líquido da Lavagem Broncoalveolar , Capsaicina , Captopril , Canais de Cátion TRPV , Animais , Captopril/farmacologia , Canais de Cátion TRPV/metabolismo , Ratos , Masculino , Bradicinina/farmacologia , Capsaicina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Ratos Sprague-Dawley , Resistência das Vias Respiratórias/efeitos dos fármacos , Antagonistas de Receptor B2 da Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Abstract Introduction In patients with chronic rhinosinusitis, conservative interventions with extended medical trials are often attempted prior to procedural treatment. Balloon sinuplasty (BSP) is an established procedure for symptomatic relief from chronic rhinosinusitis. However, data suggesting the suboptimal efficacy of prolonged medication management trials, prior to BSP, is lacking. Objectives The purpose of this study was to evaluate the efficacy of prolonged medication management trials, prior to BSP, for patients with chronic rhinosinusitis. Methods A retrospective review was performed for all adults with chronic rhinosinusitis who received extended medical management prior to their BSP at two outpatient clinics, from November 1, 2013, to June 31, 2018. The patients' Sino-Nasal Outcome Test (SNOT) scores were compared between baseline, post-medication trials, and post-BSP. Results The SNOT scores of a total of 64 patients were collected. Overall, patients showed a significant worsening of symptoms during the medication management trials from baseline (p = 0.002126) but significant improvement of symptoms after undergoing BSP (p < 0.0001). Conclusions The patient symptom burden worsened and prolonged during medication management trials. The BSP procedure alone showed significant improvement in the quality of life for chronic rhinosinusitis patients, when considering their SNOT scores. The worsening of patients' symptoms during medication management may invalidate the necessity of prolonged medication management trials.
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Introduction In patients with chronic rhinosinusitis, conservative interventions with extended medical trials are often attempted prior to procedural treatment. Balloon sinuplasty (BSP) is an established procedure for symptomatic relief from chronic rhinosinusitis. However, data suggesting the suboptimal efficacy of prolonged medication management trials, prior to BSP, is lacking. Objectives The purpose of this study was to evaluate the efficacy of prolonged medication management trials, prior to BSP, for patients with chronic rhinosinusitis. Methods A retrospective review was performed for all adults with chronic rhinosinusitis who received extended medical management prior to their BSP at two outpatient clinics, from November 1, 2013, to June 31, 2018. The patients' Sino-Nasal Outcome Test (SNOT) scores were compared between baseline, post-medication trials, and post-BSP. Results The SNOT scores of a total of 64 patients were collected. Overall, patients showed a significant worsening of symptoms during the medication management trials from baseline ( p = 0.002126) but significant improvement of symptoms after undergoing BSP ( p < 0.0001). Conclusion The patient symptom burden worsened and prolonged during medication management trials. The BSP procedure alone showed significant improvement in the quality of life for chronic rhinosinusitis patients, when considering their SNOT scores. The worsening of patients' symptoms during medication management may invalidate the necessity of prolonged medication management trials.
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BACKGROUND: The Brazilian Cohort of Asthma São Paulo (BRASASP) had a well-characterized severe asthmatic in Brazil, with 12 years of follow-up under standard treatment. METHODS: Sequential assessment of patients with uncontrolled asthma from BRASASP cohort was carried out with 12 years of follow-up, performing exams and comparing with previous measurements. RESULTS: 50 from the 60 initial patients were reevaluated. Twelve years later, FEV1 and the FEV1/FVC ratio have significantly decreased, with a rate of loss of lung function of 11.8 and 14%, respectively, and worsening in small airway parameters such as RV/TLC. BMI, The Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ) scores haven't changed. However, exacerbations decreased by 56%. Mean daily inhaled corticosteroid use was similar over time, but daily oral corticosteroid use decreased, in addition to a significant reduction in induced sputum eosinophilic and neutrophilic profile and serum IgE. Rhinitis, sinusitis, and GERD were the main comorbidities. In quality of life according to respiratory questionnaire SGRQ, total score showed a huge improvement (62% of patients). CONCLUSIONS: There was significant decrease in FEV1 and FEV1/FVC. Data of pulmonary functional small airway characteristics show globally affected airways. Although higher doses of medications, patients were still uncontrolled, but with reduction of exacerbations, daily use of oral corticosteroid, less eosinophils and neutrophils in induced sputum and lower levels of IgE. Improvement in quality of life in 62% of patients.
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Asma , Humanos , Asma/tratamento farmacológico , Qualidade de Vida , Seguimentos , Brasil , Pulmão , Eosinófilos , Corticosteroides/uso terapêutico , Imunoglobulina ERESUMO
Ferroptosis is a kind of regulated cell death, supporting the pathological process of lung inflammation, including asthma. Quercetin (QCT), a kind of natural dietary flavonoid, exerts anti-inflammatory and anti-ferroptosis effects in various diseases. However, the role of QCT in ferroptosis-associated airway inflammation of neutrophilic asthma remains to be described. Our study aimed to investigate the therapeutic effects of QCT on neutrophilic airway inflammation of asthma. Ferrostatin-1 (Fer-1), as a kind of ferroptosis inhibitor, was used to demonstrate whether neutrophilic airway inflammation of asthma relied on ferroptosis. In our study, the alleviation effect of QCT on neutrophilic airway inflammation was similar to Fer-1. Moreover, the significantly decreased levels of ferroptosis anti-oxidant protein (GPX4 and SLC7A11), increased malondialdehyde (MDA) levels, upregulated levels of 4-hydroxynonenal (4-HNE) expression by immunohistochemistry, and distorted mitochondria morphological changes in the lung tissues suggested lung ferroptosis in neutrophilic airway inflammation, which could be reversed by QCT treatment. In vitro experiments showed that QCT reduced LPS-induced ferroptosis through upregulating cell viability and levels of ferroptosis anti-oxidant protein (SLC7A11 and GPX4), reducing inflammatory cytokines, and decreasing the levels of MDA. Furthermore, ferroptosis was accompanied by enhancing M1 phenotype in neutrophilic airway inflammation, and QCT suppressed ferroptosis by inhibiting the pro-inflammatory M1 profile in vitro and in vivo, just as Fer-1 did. In conclusion, our study found that QCT ameliorated ferroptosis-associated neutrophilic airway inflammation accompanied by inhibiting M1 macrophage polarization. QCT may be a promising ferroptosis inhibitor for neutrophilic airway inflammation.
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Asma , Quercetina , Humanos , Quercetina/farmacologia , Quercetina/uso terapêutico , Antioxidantes , Macrófagos , Inflamação/tratamento farmacológicoRESUMO
Neutrophil extracellular traps (NETs) are a recently described mechanism of neutrophils that play an important role in health and disease. NETs are an innate defense mechanism that participate in clearance of pathogens, but they may also cause collateral damage in unrelated host tissues. Neutrophil dysregulation and NETosis occur in multiple lung diseases, such as pathogen-induced acute lung injury, pneumonia, chronic obstructive pulmonary disease (COPD), severe asthma, cystic fibrosis, and recently, the novel coronavirus SARS-CoV-2. More recently, research into immunometabolism has surged due to the possibility of reprogramming metabolism in order to modulate immune functions. The present review analyzes the different metabolic pathways associated with NETs formation, and how these impact on pathologies of the airways.
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COVID-19 , Fibrose Cística , Armadilhas Extracelulares , Humanos , Neutrófilos , SARS-CoV-2RESUMO
Respiratory allergies affect humans worldwide, causing extensive morbidity and mortality. They include allergic rhinitis (AR), asthma, pollen food allergy syndrome (PFAS), aspirin-exacerbated respiratory disease (AERD), and nasal polyps (NPs). The study of respiratory allergic diseases requires new technologies for early and accurate diagnosis and treatment. Omics technologies provide the tools required to investigate DNA, RNA, proteins, and other molecular determinants. These technologies include genomics, transcriptomics, proteomics, and metabolomics. However, proteomics is one of the main approaches to studying allergic disorders' pathophysiology. Proteins are used to indicate normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. In this field, the principal goal of proteomics has been to discover new proteins and use them in precision medicine. Multiple technologies have been applied to proteomics, but that most used for identifying, quantifying, and profiling proteins is mass spectrometry (MS). Over the last few years, proteomics has enabled the establishment of several proteins for diagnosing and treating respiratory allergic diseases.
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Asma , Proteômica , Genômica/métodos , Humanos , Espectrometria de Massas , Metabolômica/métodos , Proteômica/métodosRESUMO
BACKGROUND: We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. OBJECTIVES: In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. METHODS: BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. RESULTS: Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. CONCLUSIONS: Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.
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Asma , Toxoplasma , Adjuvantes Imunológicos , Animais , Asma/patologia , Asma/terapia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Elastase de Leucócito , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Inibidores de Serina Proteinase , Toxoplasma/genética , Tripsina , VacinaçãoRESUMO
Solidagenone is the main active constituent present in Solidago chilensis Meyen which is used in folk medicine to treat pain and inflammatory diseases. This study aimed to evaluate the anti-inflammatory activity of solidagenone in vitro and in a model of allergic airway inflammation. In vitro studies were performed in activated macrophages and lymphocytes. BALB/c mice were sensitized and challenged with ovalbumin and treated with solidagenone orally (30 or 90 mg/kg body weight) or dexamethasone, as a positive control in our in vivo analysis. Supernatant concentrations of nitrite, TNF and IL-1ß, as well as gene expression of pro-inflammatory mediators in macrophages cultures, were reduced after solidagenone treatment, without affecting macrophages viability. Besides, solidagenone significantly decreased T cell proliferation and secretion of IFNγ and IL-2. Th2 cytokine concentrations and inflammatory cell counts, especially eosinophils, in bronchoalveolar lavage fluid were reduced in mice treated with solidagenone. Histopathological evaluation of lung tissue was performed, and morphometrical analyses demonstrated reduction of cellular infiltration and mucus hypersecretion. Altogether, solidagenone presented anti-inflammatory activity in vitro and in vivo in the OVA-induced airway inflammation model, suggesting its promising pharmacological use as an anti-inflammatory agent for allergic hypersensitivity.
Assuntos
Anti-Inflamatórios/farmacologia , Furanos/farmacologia , Inflamação/tratamento farmacológico , Naftalenos/farmacologia , Solidago/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Líquido da Lavagem Broncoalveolar , Dexametasona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Furanos/administração & dosagem , Furanos/isolamento & purificação , Mediadores da Inflamação/metabolismo , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naftalenos/administração & dosagem , Naftalenos/isolamento & purificação , OvalbuminaAssuntos
Aspirina/efeitos adversos , Pólipos Nasais/patologia , Mucosa Respiratória/metabolismo , Doenças Respiratórias/etiologia , Doenças Respiratórias/metabolismo , Rinite/etiologia , Rinite/metabolismo , Sinusite/etiologia , Sinusite/metabolismo , Biomarcadores , Doença Crônica , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Mucosa Respiratória/patologia , Doenças Respiratórias/patologia , Rinite/patologia , Sinusite/patologiaRESUMO
The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-ß. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.
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Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Rinite Alérgica/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Receptores Histamínicos H1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Background: Summer Pasture Associated Obstructive Pulmonary Disease (SPAOPD), or Equine Pasture Asthma (EPA),has been described as an environmentally-induced respiratory disease that occurs during the warmer and more humidmonths, leading to reversible airway obstruction, persistent and non-specific airway hyper-responsiveness, and chronicneutrophilic airway inflammation. Exacerbation of clinical signs vary according to warm seasons and range from mildto severe episodes of wheezing, coughing, and laboured breathing, being highly debilitating to the equine. This reportdescribed two cases of Equine Pasture Asthma that showed clinical and environmental similarities with Summer PastureAssociated Obstructive Pulmonary Disease.Cases: The patients were crossbreed geldings that have never been stabled and were used for cattle management in a farmin southeastern Brazil. They presented poor performance and a persistent cough for over 3 years. Initially, the respiratorysigns were only observed after exercise but, over the years, it gradually progressed to being observed when the horses wereat rest. Both animals had a history of regular deworming and were previously treated by other veterinarians with antibiotics,clenbuterol, and mucokinetics. Little improvement was noticed by the owner and the signs returned over time as treatmentwas often discontinued. Clinical findings were compatible with the grade 3 mucus classification as well as with score 2for Severe Asthma. BALF cytology was done according to routine procedure. Animal 1 presented slides with free yeast,macrophages, and mucus with Curschmanns spiral and counting of 29.7% of neutrophils (NE), 43.7% of lymphocytes(LP), 25.3% of macrophages (MC) and 1.3% of eosinophils (EO). Animal 2 presented slides with phagocytized yeast,mucus and counting of 27% of NE, 38.5% of LP, 33% of MC and 1.5% of EO...(AU)
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Animais , Doenças dos Cavalos , Asma/veterinária , Triancinolona Acetonida/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêuticoRESUMO
Background: Summer Pasture Associated Obstructive Pulmonary Disease (SPAOPD), or Equine Pasture Asthma (EPA),has been described as an environmentally-induced respiratory disease that occurs during the warmer and more humidmonths, leading to reversible airway obstruction, persistent and non-specific airway hyper-responsiveness, and chronicneutrophilic airway inflammation. Exacerbation of clinical signs vary according to warm seasons and range from mildto severe episodes of wheezing, coughing, and laboured breathing, being highly debilitating to the equine. This reportdescribed two cases of Equine Pasture Asthma that showed clinical and environmental similarities with Summer PastureAssociated Obstructive Pulmonary Disease.Cases: The patients were crossbreed geldings that have never been stabled and were used for cattle management in a farmin southeastern Brazil. They presented poor performance and a persistent cough for over 3 years. Initially, the respiratorysigns were only observed after exercise but, over the years, it gradually progressed to being observed when the horses wereat rest. Both animals had a history of regular deworming and were previously treated by other veterinarians with antibiotics,clenbuterol, and mucokinetics. Little improvement was noticed by the owner and the signs returned over time as treatmentwas often discontinued. Clinical findings were compatible with the grade 3 mucus classification as well as with score 2for Severe Asthma. BALF cytology was done according to routine procedure. Animal 1 presented slides with free yeast,macrophages, and mucus with Curschmanns spiral and counting of 29.7% of neutrophils (NE), 43.7% of lymphocytes(LP), 25.3% of macrophages (MC) and 1.3% of eosinophils (EO). Animal 2 presented slides with phagocytized yeast,mucus and counting of 27% of NE, 38.5% of LP, 33% of MC and 1.5% of EO...
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Animais , Asma/veterinária , Doenças dos Cavalos , Triancinolona Acetonida/uso terapêutico , /uso terapêuticoRESUMO
It is largely known that photobiomodulation (PBM) has beneficial effects on allergic pulmonary inflammation. Our previous study showed an anti-inflammatory effect of the PBM in an acute experimental model of asthma, and we see that this mechanism is partly dependent on IL-10. However, it remains unclear whether the activation of regulatory T cells is mediated by PBM in a chronic experimental model of asthma. In this sense, the objective of this study was to verify the anti-inflammatory role of the PBM in the pulmonary inflammatory response in a chronic experimental asthma model. The protocol used for asthma induction was the administration of OVA subcutaneously (days 0 and 14) and intranasally (3 times/week, for 5 weeks). On day 50, the animals were sacrificed for the evaluation of the different parameters. The PBM used was the diode, with a wavelength of 660 nm, a power of 100 mW, and 5 J for 50 s/point, in three different application points. Our results showed that PBM decreases macrophages, neutrophils, and lymphocytes in the bronchoalveolar lavage fluid (BALF). Moreover, PBM decreased the release of cytokines by the lung, mucus, and collagen in the airways and pulmonary mechanics. When we analyzed the percentage of Treg cells in the group irradiated with laser, we verified an increase in these cells, as well as the release of IL-10 in the BALF. Therefore, we conclude that the use of PBM therapy in chronic airway inflammation attenuated the inflammatory process, as well as the pulmonary functional and structural parameters, probably due to an increase in Treg cells.
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Asma , Interleucina-10 , Terapia com Luz de Baixa Intensidade , Animais , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Asma/radioterapia , Linfócitos T CD4-Positivos , Modelos Animais de Doenças , Fatores de Transcrição Forkhead , Inflamação , Interleucina-10/metabolismo , Pulmão , Camundongos , Camundongos Endogâmicos BALB C , OvalbuminaRESUMO
The objective of this study was to investigate the inhibitory effect of miR-135a in regulating JAK/STAT signaling pathway on airway inflammation in asthmatic mice. An asthma model was established by sensitization and stimulation with ovalbumin (OVA), and the corresponding drug intervention was given from the day of stimulation by means of nasal drops. Airway hyperresponsiveness was tested. The content of miR-135a in the lung tissue of mice was detected by RT-PCR. The pathological changes of lung tissue were evaluated by HE staining. Tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-5, and eotaxin in bronchoalveolar lavage fluid (BALF) and lung tissue were detected by ELISA and immunohistochemistry, respectively. The expression of JAK/STAT signaling pathway-related protein in lung tissue was detected by western blot. To further validate the effect of miR-135a overexpression on the JAK/STAT signaling pathway, pathway activators and inhibitors were added. Compared with the OVA group, the airway hyperresponsiveness of the mice was significantly decreased after treatment with the miR-135a agonist. The expression of miR-135a was significantly increased in the lung tissue and the pathological changes of the lung tissue were alleviated. The contents of TNF-α, IL-6, IL-5, and eotaxin in BALF and lung tissues were decreased. The expression of JAK/STAT signaling pathway-related proteins p-JAK3/JAK3, p-STAT1/STAT1, and p-STAT3/STAT3 were significantly reduced in lung tissue (P<0.05). Addition of JAK inhibitor AG490 reduced airway inflammation in asthmatic mice. miR-135a agonists inhibit airway inflammation in asthmatic mice by regulating the JAK/STAT signaling pathway.
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Animais , Ratos , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar , Transdução de Sinais , Ovalbumina , MicroRNAs , Modelos Animais de Doenças , Pulmão , Camundongos Endogâmicos BALB CRESUMO
Carvone is a monoterpene found in nature in the form of enantiomers (S- and R-). While previous research has demonstrated the anti-inflammatory and anti-allergic effects of carvone, the influence of carvone enantiomeric composition on its anti-allergic activity remains to be investigated. This study aimed to evaluate the anti-allergic activity of carvone enantiomers in a murine model of airway allergic inflammation induced by sensitization and challenge with ovalbumin (OVA). The oral treatment with R-carvone or S-carvone 1 h before each challenge inhibited the number of leukocytes and eosinophils in the bronchoalveolar lavage (BAL). R-carvone inhibited leukocyte infiltration and mucus production in the lung, which was correlated with decreased production of OVA-specific IgE in the serum and increased concentrations of IL-10 in the BAL. On the other hand, the administration of S-carvone had little inhibitory effect on inflammatory infiltration and mucus production in the lung, which might be associated with increased production of IFN-γ in the BAL. When administered 1 h before each sensitization, both enantiomers inhibited eosinophil recruitment to the BAL but failed in decreasing the titers of IgE in the serum of allergic mice. Our data indicate that carvone enantiomers differentially modulated IgE-mediated airway inflammation in mice. In conclusion, unlike S-carvone, R-carvone has the potential to be used in anti-allergic drug development.
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Anti-Inflamatórios/farmacologia , Monoterpenos Cicloexânicos/farmacologia , Imunoglobulina E/imunologia , Imunomodulação/efeitos dos fármacos , Inflamação/imunologia , Doenças Respiratórias/imunologia , Animais , Anti-Inflamatórios/química , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Monoterpenos Cicloexânicos/química , Citocinas/biossíntese , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/metabolismo , Doenças Respiratórias/patologia , Índice de Gravidade de DoençaRESUMO
In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n-hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski's rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg-1) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg-1). As for lung function parameters, biseugenol (20 mg·kg-1) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice.
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Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Granulócitos/patologia , Éteres Fenílicos/farmacologia , Animais , Antiasmáticos/química , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Asma/complicações , Asma/fisiopatologia , Disponibilidade Biológica , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Simulação por Computador , Modelos Animais de Doenças , Granulócitos/efeitos dos fármacos , Inflamação/complicações , Inflamação/tratamento farmacológico , Lignanas/química , Lignanas/farmacologia , Lignanas/uso terapêutico , Modelos Lineares , Masculino , Camundongos Endogâmicos BALB C , Éteres Fenílicos/química , Éteres Fenílicos/uso terapêutico , Testes de Função Respiratória , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/fisiopatologiaRESUMO
BACKGROUND: Aerobic training and breathing exercises are interventions that improve asthma control. However, the outcomes of these 2 interventions have not been compared. OBJECTIVE: To compare the effects of aerobic training versus breathing exercises on clinical control (primary outcome), quality of life, exercise capacity, and airway inflammation in outpatients with moderate-to-severe asthma. METHODS: Fifty-four asthmatics were randomized into either the aerobic training group (AG, n = 29) or the breathing exercise group (BG, n = 25). Both interventions lasted for 24 sessions (2/week, 40 minutes/session). Asthma clinical control (Asthma Control Questionnaire [ACQ]), quality of life (Asthma Quality of Life Questionnaire), asthma symptom-free days (ASFD), airway inflammation, exercise capacity, psychological distress (Hospital Anxiety and Depression Scale), daily-life physical activity (DLPA), and pulmonary function were evaluated before, immediately after, and 3 months after the intervention. RESULTS: Both interventions presented similar results regarding the ACQ score, psychological distress, ASFD, DLPA, and airway inflammation (P > .05). However, participants in the AG were 2.6 times more likely to experience clinical improvement at the 3-month follow-up than participants in the BG (P = .02). A greater proportion of participants in the AG also presented a reduction in the number of days without rescue medication use compared with BG (34% vs 8%; P = .04). CONCLUSIONS: Outpatients with moderate-to-severe asthma who participated in aerobic training or breathing exercise programs presented similar results in asthma control, quality of life, asthma symptoms, psychological distress, physical activity, and airway inflammation. However, a greater proportion of participants in the AG presented improvement in asthma control and reduced use of rescue medication.
Assuntos
Asma , Qualidade de Vida , Asma/terapia , Exercícios Respiratórios , Exercício Físico , Terapia por Exercício , HumanosRESUMO
The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via α7 nicotinic receptor (α7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU-282987(0.5-to-2mg/kg),(α7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, α7nAChR antagonist) to confirm that the effects observed by PNU were due to α7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pre-treatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3-phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, α7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly α7nAChR should be further considered as a therapeutic target in asthma.
Assuntos
Asma/imunologia , Proteínas Vesiculares de Transporte de Acetilcolina/deficiência , Receptor Nicotínico de Acetilcolina alfa7/imunologia , Remodelação das Vias Aéreas , Alérgenos , Animais , Asma/etiologia , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Doença Crônica , Citocinas/imunologia , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/imunologia , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Ovalbumina , Fator de Transcrição STAT3/antagonistas & inibidores , Proteína 3 Supressora da Sinalização de Citocinas/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Receptor Nicotínico de Acetilcolina alfa7/agonistasRESUMO
Asthma is characterized by the influx of inflammatory cells, especially of eosinophils as well as reactive oxygen species (ROS) production, driven by the release of the T helper 2 (Th2)-cell-associated cytokines. The cholinergic anti-inflammatory pathway (CAP) inhibit cytokines production and controls inflammation. Thus, we investigated the effects of pharmacological activation of CAP by neostigmine on oxidative stress and airway inflammation in an allergic asthma model. After the OVA challenge, mice were treated with neostigmine. We showed that CAP activation by neostigmine reduced the levels of pro-inflammatory cytokines (IL-4, IL-5, IL-13, IL-1ß, and TNF-α), which resulted in a decrease of eosinophils influx. Furthermore, neostigmine also conferred airway protection against oxidative stress, attenuating ROS production through the increase of antioxidant defense, evidenced by the catalase (CAT) activity. We propose, for the first time, that pharmacological activation of the CAP can lead to new possibilities in the therapeutic management of allergic asthma.