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Shortening of airway smooth muscle and bronchoconstriction are pathognomonic for asthma. Airway shortening occurs through calcium-dependent activation of myosin light chain kinase, and RhoA-dependent calcium sensitization, which inhibits myosin light chain phosphatase. The mechanism through which pro-contractile stimuli activate calcium sensitization is poorly understood. Our review of the literature suggests that pro-contractile G protein coupled receptors likely signal through G12/13 to activate RhoA and mediate calcium sensitization. This hypothesis is consistent with the effects of pro-contractile agonists on RhoA and Rho kinase activation, actin polymerization and myosin light chain phosphorylation. Recognizing the likely role of G12/13 signaling in the pathophysiology of asthma rationalizes the effects of pro-contractile stimuli on airway hyperresponsiveness, immune activation and airway remodeling, and suggests new approaches for asthma treatment.
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Asma , Transdução de Sinais , Asma/metabolismo , Asma/fisiopatologia , Asma/tratamento farmacológico , Humanos , Transdução de Sinais/fisiologia , Animais , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Músculo Liso/metabolismo , Músculo Liso/fisiopatologia , Músculo Liso/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologiaRESUMO
Aconitum heterophyllum Wall ex Royle. (Ranunculaceae) is a traditional medicinal herb that has shown extensive pharmacological potential to treat cough, diarrhea, and infectious diseases but no scientific evidence is available to validate its antiasthmatic potential. In this study, we have investigated the tracheal relaxation and antiasthmatic activity of the selected bioactive fraction of A. heterophyllum. Chemical profiling of the most effective fraction obtained via bioassay-guided fractionation was done using LC-MS (Liquid chromatography-mass spectrometry, a technique utilized in the identification, separation, and quantification of known and unknown compounds). Molecular docking analysis of characterized constituents was performed to recognize the binding receptors, followed by an evaluation of the tracheal relaxation ability of active fraction. An acute oral toxicity study of the most effective fraction was done using OECD guidelines 423. Further, the therapeutic efficacy of the fraction was validated in asthma using a guinea pig model of ovalbumin (OVA) induced allergic asthma. The bio-guided activity revealed that hydro-methanolic extract of A. heterophyllum roots (F-1) was the most active fraction. LC-MS analysis of F-1 showed the presence of six major bioactive compounds in F-1. Molecular docking studies revealed strong binding affinities of identified constituents with histaminic receptor (H1) and muscarinic receptor (M3). The ex vivo study demonstrated smooth muscle relaxant activity of F-1 via dysregulating diverse signal transduction pathways viz. histaminic and muscarinic receptors antagonism (non-competitive), stimulation of ß2-adrenergic receptor pathway, and soluble guanylyl cyclase activation. The findings of acute oral toxicity studies revealed that F-1 had no toxicity up to the dose of 2000 mg/Kg. The anti-asthmatic therapeutic efficacy of F-1 was further confirmed by the amelioration of respiratory hyperresponsiveness in asthmatic guinea pigs. This is the first evidence-based study showing the antiasthmatic therapeutic potential of the traditionally used herb A. heterophyllum through, computational and animal studies.
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BACKGROUND: Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4ß7 and fibronectin induces myofibroblast differentiation via this receptor. OBJECTIVES: To investigate the role of the ß7 integrin receptor subunit and α4ß7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. METHODS: C57BL/6 wild type (WT) and ß7 integrin null mice (ß7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4ß7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-ß (TGFß) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and ß7 -/- saline (SAL) and OVA treated mice was evaluated. RESULTS: Eosinophil numbers were similar in WT vs ß7-/- mice. Prolonged OVA exposure in ß7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFß and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4ß7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not ß7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in ß7-/- fibroblasts relative to WT. CONCLUSIONS: The ß7 integrin subunit and the α4ß7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation.
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Remodelação das Vias Aéreas , Cadeias beta de Integrinas , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Animais , Remodelação das Vias Aéreas/fisiologia , Remodelação das Vias Aéreas/imunologia , Camundongos , Ovalbumina/toxicidade , Cadeias beta de Integrinas/metabolismo , Cadeias beta de Integrinas/genética , Alérgenos/imunologia , Alérgenos/toxicidade , Células Cultivadas , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/patologia , Pulmão/metabolismo , Pulmão/imunologia , Pulmão/patologia , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Supplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease.
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Fatores de Transcrição ARNTL , Animais Recém-Nascidos , Hiperóxia , Animais , Hiperóxia/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Camundongos , Feminino , Masculino , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Caracteres SexuaisRESUMO
Chronic cough is a common disorder lasting more than 8 weeks and affecting all age groups. The evidence supporting the role of neutrophils in chronic cough pathology is based on many patients with chronic cough developing airway neutrophilia. How neutrophils influence the development of chronic cough is unknown. However, they are likely involved in multiple aspects of cough etiology, including promoting airway inflammation, airway remodeling, hyper-responsiveness, local neurogenic inflammation, and other possible mechanisms. Neutrophilic airway inflammation is also associated with refractory cough, poor control of underlying diseases (e.g., asthma), and insensitivity to cough suppressant therapy. The potential for targeting neutrophils in chronic cough needs exploration, including developing new drugs targeting one or more neutrophil-mediated pathways or altering the neutrophil phenotype to alleviate chronic cough. How the airway microbiome differs, plays a role, and interacts with neutrophils in different cough etiologies is poorly understood. Future studies should focus on understanding the relationship between the airway microbiome and neutrophils.
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BACKGROUND: Particulate ß-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown. METHODS: C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF). RESULTS: The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF. CONCLUSION: These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.
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Asma , Modelos Animais de Doenças , Mastócitos , Camundongos Endogâmicos C57BL , beta-Glucanas , Animais , Asma/imunologia , Asma/tratamento farmacológico , Asma/patologia , Mastócitos/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Administração Oral , beta-Glucanas/farmacologia , beta-Glucanas/administração & dosagem , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Ovalbumina/imunologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/efeitos dos fármacosRESUMO
High serum estrogen concentrations are associated with asthma development and severity, suggesting a link between estradiol and airway hyperresponsiveness (AHR). 17ß-estradiol (E2) has non-genomic effects via Ca2+ regulatory mechanisms; however, its effect on the plasma membrane Ca2+-ATPases (PMCA1 and 4) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) is unknown. Hence, in the present study, we aim to demonstrate if E2 favors AHR by increasing intracellular Ca2+ concentrations in guinea pig airway smooth muscle (ASM) through a mechanism involving Ca2+-ATPases. In guinea pig ASM, Ca2+ microfluorometry, muscle contraction, and Western blot were evaluated. Then, we performed molecular docking analysis between the estrogens and Ca2+ ATPases. In tracheal rings, E2 produced AHR to carbachol. In guinea pig myocytes, acute exposure to physiological levels of E2 modified the transient Ca2+ peak induced by caffeine to a Ca2+ plateau. The incubation with PMCA inhibitors (lanthanum and carboxyeosin, CE) partially reversed the E2-induced sustained plateau in the caffeine response. In contrast, cyclopiazonic acid (SERCA inhibitor), U-0126 (an inhibitor of ERK 1/2), and choline chloride did not modify the Ca2+ plateau produced by E2. The mitochondrial uniporter activity and the capacitative Ca2+ entry were unaffected by E2. In guinea pig ASM, Western blot analysis demonstrated PMCA1 and PMCA4 expression. The results from the docking modeling demonstrate that E2 binds to both plasma membrane ATPases. In guinea pig tracheal smooth muscle, inhibiting the PMCA with CE, induced hyperresponsiveness to carbachol. 17ß-estradiol produces hyperresponsiveness by inhibiting the PMCA in the ASM and could be one of the mechanisms responsible for the increase in asthmatic crisis in women.
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Cálcio , Estradiol , Simulação de Acoplamento Molecular , ATPases Transportadoras de Cálcio da Membrana Plasmática , Animais , Cobaias , Estradiol/farmacologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Cálcio/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Masculino , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Contração Muscular/efeitos dos fármacos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Carbacol/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Lung function reaches a peak/plateau in early adulthood before declining with age. Lower early adult lung function may increase the risk for chronic obstructive pulmonary disease (COPD) in mid-late adult life. Understanding the effects of multiple childhood/adolescent exposures and their potential interactions on plateau lung function would provide insights into the natural history of COPD. METHODS: Longitudinal spirometry data from 688 participants with complete data from a population-based birth cohort (original n = 1037) were used to investigate associations between a wide range of childhood/adolescent exposures and repeated measures of FEV1, FVC and FEV1/FVC during the early-adult plateau phase. Generalized estimating equations were used to accommodate the multiple timepoints per participant. RESULTS: FEV1 reached a peak/plateau between ages 18 and 26 and FVC from 21 to 32 years, whereas FEV1/FVC declined throughout early adulthood. Childhood asthma and airway hyperresponsiveness were associated with lower early adult FEV1 and FEV1/FVC. Smoking by age 18 was associated with lower FEV1/FVC. Higher BMI during early adulthood was associated with lower FEV1 and FVC and lower FEV1/FVC. Physical activity during adolescence was positively associated with FEV1 and FEV1/FVC but this was only statistically significant in men. There was no convincing evidence of interactions between exposures. CONCLUSION: Childhood asthma and airway hyperresponsiveness are associated with lower lung function in early adulthood. Interventions targeting these may reduce the risk of COPD in mid-late adult life. Promotion of physical activity during adolescence, prevention of cigarette smoking and maintenance of a healthy body weight in early adulthood are also priorities.
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RATIONALE: Diesel engine exhaust (DEE) is associated with the development and exacerbation of asthma. Studies have shown that DEE can aggravate allergen-induced eosinophilic inflammation in lung. However, it remains not clear that whether DEE alone could initiate non-allergic eosinophilic inflammation and airway hyperresponsiveness (AHR) through innate lymphoid cells (ILCs) pathway. OBJECTIVE: This study aims to investigate the airway inflammation and hyperresponsiveness and its relationship with ILC after DEE exposure. METHOD: Non-sensitized BALB/c mice were exposed in the chamber of diesel exhaust or filtered air for 2, 4, and 6 weeks (4â¯h/day, 6 days/week). Anti-CD4 mAb or anti-Thy1.2 mAb was administered by intraperitoneal injection to inhibit CD4+T or ILCs respectively. AHRãairway inflammation and ILCs were assessed. RESULT: DEE exposure induced significantly elevated level of neutrophils, eosinophils, collagen content at 4, 6 weeks. Importantly, the airway AHR was only significant in the 4weeks-DEE exposure group. No difference of the functional proportions of Th2 cells was found between exposure group and control group. The proportions of IL-5+ILC2, IL-17+ILC significantly increased in 2, 4weeks-DEE exposure group. After depletion of CD4+T cells, both the proportion of IL-5+ILC2 and IL-17A ILCs was higher in the 4weeks-DEE exposure group which induced AHR, neutrophilic and eosinophilic inflammation accompanied by the IL-5, IL-17A levels. CONCLUSION: Diesel engine exhaust alone can imitate asthmatic characteristics in mice model. Lung-resident ILCs are one of the major effectors cells responsible for a mixed Th2/Th17 response and AHR.
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Poluentes Atmosféricos , Linfócitos , Camundongos Endogâmicos BALB C , Emissões de Veículos , Animais , Emissões de Veículos/toxicidade , Camundongos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Poluentes Atmosféricos/toxicidade , Inflamação/induzido quimicamente , Eosinófilos/imunologia , Eosinófilos/efeitos dos fármacos , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Feminino , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , MasculinoRESUMO
Galectins are a group of ß-galactoside-binding proteins with several roles in immune response, cellular adhesion, and inflammation development. Current evidence suggest that these proteins could play a crucial role in many respiratory diseases such as pulmonary fibrosis, lung cancer, and respiratory infections. From this standpoint, an increasing body of evidence have recognized galectins as potential biomarkers involved in several aspects of asthma pathophysiology. Among them, galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-10 (Gal-10) are the most extensively studied in human and animal asthma models. These galectins can affect T helper 2 (Th2) and non-Th2 inflammation, mucus production, airway responsiveness, and bronchial remodeling. Nevertheless, while higher Gal-3 and Gal-9 concentrations are associated with a stronger degree of Th-2 phlogosis, Gal-10, which forms Charcot-Leyden Crystals (CLCs), correlates with sputum eosinophilic count, interleukin-5 (IL-5) production, and immunoglobulin E (IgE) secretion. Finally, several galectins have shown potential in clinical response monitoring after inhaled corticosteroids (ICS) and biologic therapies, confirming their potential role as reliable biomarkers in patients with asthma.
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We executed this study to determine if chemerin-like receptor 1 (CMKLR1), a Gi/o protein-coupled receptor expressed by leukocytes and non-leukocytes, contributes to the development of phenotypic features of non-atopic asthma, including airway hyperresponsiveness (AHR) to acetyl-ß-methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non-atopic asthma in wild-type mice and mice incapable of expressing CMKLR1 (CMKLR1-deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non-atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi-functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1-deficient as compared to wild-type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype-related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype-related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.
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Asma , Ozônio , Pneumonia , Animais , Camundongos , Masculino , Ozônio/efeitos adversos , Adiponectina/farmacologia , Pulmão , Pneumonia/induzido quimicamente , Líquido da Lavagem Broncoalveolar , Receptores Acoplados a Proteínas G , Asma/genética , Quimiocinas/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologiaRESUMO
Purpose: This retrospective study investigates the influence of overweight and obesity status on pulmonary function, airway inflammatory markers, and airway responsiveness in elderly asthma patients. Methods: Patients with asthma older than 65 years old who completed a bronchial provocation test (BPT) or bronchial dilation test (BDT) and a fractional exhaled nitric oxide (FeNO) test between December 2015 and June 2020 were identified retrospectively for this study. All of the patients were categorized into overweight/obesity and non-obesity groups based on their BMI. Pulmonary function test (PFT) and FeNO measurements were accomplished according to the 2014 recommendations of the Chinese National Guidelines of Pulmonary Function Test and American Thoracic Society/European Respiratory Society recommendations, respectively. Results: A total of 136 patients with an average age of 71.2 ± 5.40 years were identified. The average BMI was 23.8 ± 3.63, while the value of FeNO was 42.3 ± 38.4 parts per billion (ppb). In contrast to the non-obesity group, which had a value of 48.8 ± 43.1 ppb for FeNO, the overweight/obesity group had a significant lower value of 35.4 ± 31.4 ppb. There was no significant difference in the proportion of individuals with high airway hyperresponsiveness between the overweight/obesity and non-obesity groups (96 patients in total). Multiple linear regression analysis established an inverse correlation between FeNO and Provocation concentration causing a 20% fall in FEV1(PC20) but excluded significant relationships with age and BMI. The model's R is 0.289, and its p value is 0.045. Conclusion: The elderly Chinese Han asthmatics with overweight/obesity had lower FeNO levels than those with non-obese according to our findings. In addition, the FeNO level was inversely correlated between FeNO levels and PC20 in elderly asthmatics.
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Asma , Óxido Nítrico , Obesidade , Sobrepeso , Idoso , Feminino , Humanos , Masculino , Povo Asiático , Asma/fisiopatologia , Asma/metabolismo , Asma/diagnóstico , Índice de Massa Corporal , Testes Respiratórios , Testes de Provocação Brônquica , China/epidemiologia , Teste da Fração de Óxido Nítrico Exalado , Óxido Nítrico/metabolismo , Óxido Nítrico/análise , Obesidade/fisiopatologia , Obesidade/metabolismo , Sobrepeso/fisiopatologia , Sobrepeso/metabolismo , Testes de Função Respiratória , Hipersensibilidade Respiratória/fisiopatologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/diagnóstico , Estudos RetrospectivosRESUMO
INTRODUCTION: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. METHODS: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). RESULTS: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. CONCLUSION: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.
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Citocinas , Camundongos Knockout , Ovalbumina , Receptores Imunológicos , Receptores de Prostaglandina , Animais , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Camundongos , Ovalbumina/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Pulmão/patologia , Pulmão/imunologia , Asma/imunologia , Asma/patologia , Asma/metabolismo , Células Th2/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Eosinófilos/imunologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/etiologia , Mastócitos/imunologia , Mastócitos/metabolismo , Inflamação/imunologia , Camundongos Endogâmicos C57BLRESUMO
Obesity is a contributing factor to asthma severity; while it has long been understood that obesity is related to greater asthma burden, the mechanisms though which this occurs have not been fully elucidated. One common explanation is that obesity mechanically reduces lung volume through accumulation of adipose tissue external to the thoracic cavity. However, it has been recently demonstrated that there is substantial adipose tissue within the airway wall itself, and that the presence of adipose tissue within the airway wall is related to body mass index. This suggests the possibility of an additional mechanism by which obesity may worsen asthma, namely by altering the behaviour of the airways themselves. To this end, we modify Anafi & Wilson's classic model of the bistable terminal airway to incorporate adipose tissue within the airway wall in order to answer the question of how much adipose tissue would be required in order to drive substantive functional changes. This analysis suggests that adipose tissue within the airway wall on the order of 1%-2% of total airway cross-sectional area could be sufficient to drive meaningful changes, and further that these changes may interact with volume effects to magnify the overall burden.
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Tecido Adiposo , Asma , Modelos Biológicos , Obesidade , Tecido Adiposo/metabolismo , Humanos , Asma/fisiopatologia , Obesidade/fisiopatologia , Obesidade/metabolismo , Pulmão/fisiologiaRESUMO
PURPOSE: Extracellular acidification is a major component of tissue inflammation, including airway inflammation in asthmatics. However, its physiological/pathophysiological significance in bronchial function is not fully understood. Currently, the functional role of extracellular acidification on bronchial contraction was explored. METHODS: Left main bronchi were isolated from male BALB/c mice. Epithelium-removed tissues were exposed to acidic pH under submaximal contraction induced by 10-5 M acetylcholine in the presence or absence of a COX inhibitor indomethacin (10-6 M). Effects of AH6809 (10-6 M, an EP2 receptor antagonist), BW A868C (10-7 M, a DP receptor antagonist) and CAY10441 (3×10-6 M, an IP receptor antagonist) on the acidification-induced change in tension were determined. The release of prostaglandin E2 (PGE2) from epithelium-denuded tissues in response to acidic pH was assessed using an ELISA. RESULTS: In the bronchi stimulated with acetylcholine, change in the extracellular pH from 7.4 to 6.8 caused a transient augmentation of contraction followed by a sustained relaxing response. The latter inhibitory response was abolished by indomethacin and AH6809 but not by BW A868C or CAY10441. Both indomethacin and AH6809 significantly increased potency and efficacy of acetylcholine at pH 6.8. Stimulation with low pH caused an increase in PGE2 release from epithelium-denuded bronchi. Interestingly, the acidic pH-induced bronchial relaxation was significantly reduced in a murine asthma model that had a bronchial hyperresponsiveness to acetylcholine. CONCLUSION: Taken together, extracellular acidification could inhibit the bronchial contraction via autocrine activation of EP2 receptors. The diminished acidic pH-mediated inhibition of bronchial tone may contribute to excessive bronchoconstriction in inflamed airways such as asthma.
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Acetilcolina , Asma , Compostos de Benzil , Imidazóis , Animais , Masculino , Camundongos , Acetilcolina/farmacologia , Brônquios , Dinoprostona/metabolismo , Concentração de Íons de Hidrogênio , Indometacina/farmacologia , Inflamação , Contração Muscular , Camundongos Endogâmicos BALB CRESUMO
Asthma is a heterogeneous inflammatory disease of the airways, affecting many children, adolescents, and adults worldwide. Up to 10% of people with asthma have severe disease, associated with a higher risk of hospitalizations, greater healthcare costs, and poorer outcomes. Patients with severe asthma generally require high-dose inhaled corticosteroids and additional controller medications to achieve disease control; however, many patients remain uncontrolled despite this intensive treatment. The treatment of severe uncontrolled asthma has improved with greater understanding of asthma pathways and phenotypes as well as the advent of targeted biologic therapies. Tezepelumab, a monoclonal antibody, blocks thymic stromal lymphopoietin, an epithelial cytokine that has multifaceted effects on the initiation and persistence of asthma inflammation and pathophysiology. Unlike other biologic treatments, tezepelumab has demonstrated efficacy across severe asthma phenotypes, with the magnitude of effects varying by phenotype. Here we describe the anti-inflammatory effects and efficacy of tezepelumab across the most relevant phenotypes of severe asthma. Across clinical studies, tezepelumab reduced annualized asthma exacerbation rates versus placebo by 63-71% in eosinophilic severe asthma, by 58-68% in allergic severe asthma, by 67-71% in allergic and eosinophilic severe asthma, by 34-49% in type 2-low asthma, and by 31-41% in oral corticosteroid-dependent asthma. Furthermore, in all these asthma phenotypes, tezepelumab demonstrated higher efficacy in reducing exacerbations requiring hospitalizations or emergency department visits versus placebo. In patients with severe uncontrolled asthma, who commonly have multiple drivers of inflammation and disease, tezepelumab may modulate airway inflammation more extensively, as other available biologics block only specific downstream components of the inflammatory cascade.
Asthma is characterized by an immune response leading to airway inflammation. People with severe asthma may react to different triggers and develop different types of airway inflammation. In patients with asthma, a protein called thymic stromal lymphopoietin (TSLP) plays an important role in the immune response that leads to the signs and symptoms of asthma. TSLP is released by the airway lining in response to different asthma triggers, driving an immune chain reaction, leading to airway narrowing and tightening, increased airway inflammation, worsening asthma symptoms, and asthma attack. Tezepelumab is a monoclonal antibody (a type of protein) that prevents TSLP from attaching to its receptor, thereby blocking its activity, reducing airway inflammation and asthma symptoms. Tezepelumab is an add-on medicine for the treatment of people aged 12 years or older with severe asthma that is not controlled with their current medicines. In this article, we discuss how tezepelumab may work in different types of asthma, for example allergic asthma, eosinophilic asthma, and T2-low asthma. We also describe how effective tezepelumab is in these different asthma types, through the reduction of asthma attacks and improvement in lung function, symptom control, and quality of life, leading to fewer emergency department visits and hospitalizations for asthma.
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BACKGROUND: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. METHODS: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. RESULTS: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. CONCLUSIONS: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.
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Anticorpos Monoclonais Humanizados , Asma , Índice de Gravidade de Doença , Humanos , Asma/tratamento farmacológico , Asma/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto , Idoso , Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/uso terapêutico , Antiasmáticos/farmacologia , Qualidade de Vida , Tomografia Computadorizada por Raios X , Testes de Função RespiratóriaRESUMO
Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2, and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.
Assuntos
Asma , Mucosa Respiratória , Humanos , Asma/imunologia , Asma/fisiopatologia , Animais , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Citocinas/metabolismo , Citocinas/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Mastócitos/imunologia , BroncoconstriçãoRESUMO
Between 5 and 10% of asthma patients do not respond to glucocorticoid therapy. Experimental animal models are indispensable for investigating the pathogenesis of steroid-resistant asthma; however, the majority of murine asthma models respond well to glucocorticoids. We previously reported that multiple intratracheal administration of ovalbumin (OVA) at a high dose (500 µg/animal) induced steroid-insensitive airway eosinophilia and remodeling with lung fibrosis, whereas a low dose (5 µg/animal) caused steroid-sensitive responses. The aims of the present study were as follows: 1) to clarify whether airway hyperresponsiveness (AHR) in the two models is also insensitive and sensitive to a glucocorticoid, respectively, and 2) to identify steroid-insensitive genes encoding extracellular matrix (ECM) components and pro-fibrotic factors in the lung. In comparisons with non-challenged group, the 5- and 500-µg OVA groups both exhibited AHR to methacholine. Daily intraperitoneal treatment with dexamethasone (1 mg/kg) significantly suppressed the development of AHR in the 5-µg OVA group, but not in the 500-µg OVA group. Among genes encoding ECM components and pro-fibrotic factors, increased gene expressions of fibronectin and collagen types I, III, and IV as ECM components as well as 7 matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, transforming growth factor-ß1, and activin A/B as pro-fibrotic factors were insensitive to dexamethasone in the 500-µg OVA group, but were sensitive in the 5-µg OVA group. In conclusion, steroid-insensitive AHR developed in the 500-µg OVA group and steroid-insensitive genes encoding ECM components and pro-fibrotic factors were identified. Drugs targeting these molecules have potential in the treatment of steroid-resistant asthma.
Assuntos
Asma , Hipersensibilidade Respiratória , Humanos , Animais , Camundongos , Glucocorticoides , Inibidor Tecidual de Metaloproteinase-1 , Asma/tratamento farmacológico , Asma/genética , Esteroides , Ovalbumina , Pulmão , Matriz Extracelular , Expressão Gênica , Dexametasona/farmacologia , Dexametasona/uso terapêuticoRESUMO
OBJECTIVE: The function of Bcl-6 in T follicular helper (Tfh) cell maturation is indispensable, and Tfh cells play a pivotal role in asthma. This study investigated the impact of Bcl-6 on asthmatic traits. METHODS: The microscopic pathological alterations, airway resistance (AR), and lung compliance (LC) were determined in asthmatic mice and Bcl-6 interference mice. The surface molecular markers of Tfh cells and the Bcl-6 mRNA and protein expression were determined by flow cytometry, RT-qPCR, and Western blotting, respectively. The relationships between the Tfh cell ratio and the IgE and IgG1 concentrations in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage fluid (BALF) were determined. RESULTS: Asthmatic inflammatory changes were observed in the lung tissue and were attenuated by Bcl-6 siRNA and dexamethasone (DXM). Asthmatic mice exhibited an increased AR and a decreased LC, while Bcl-6 siRNA or DXM mitigated these changes. The percentages of Tfh cells and eosinophils were significantly increased in the asthmatic mice, and they significantly decreased after Bcl-6 inhibition or DXM treatment. RT-qPCR and Western blotting analyses revealed that the Bcl-6 expression level in PBMCs was significantly higher in asthmatic mice, and it decreased following Bcl-6 inhibition or DXM treatment. The IgE expression in the serum and BALF and the B cell expression in PBMCs exhibited a similar trend. In asthmatic mice, the ratio of Tfh cells in the peripheral blood showed a strong positive correlation with the IgE levels in the serum and BALF, but not with the IgG1 levels. CONCLUSION: The amelioration of airway inflammation and airway hyper-responsiveness is achieved through Bcl-6 suppression, which effectively hinders Tfh cell differentiation, ultimately resulting in a concurrent reduction in IgE production.