RESUMO
Approximately 1-third of patients with severe asthma are candidates for both omalizumab and mepolizumab treatment. We aimed to compare the clinical, spirometric and inflammatory efficacy of these 2 biologics in atopic and eosinophilic "overlap" severe asthma patients. In our 3-center retrospective cross-sectional observational study, the data of patients who received omalizumab or mepolizumab for at least 16 weeks to treat severe asthma were examined. Atopic (perennial allergen sensitivity and total IgE level 30-1500 IU/mL) and eosinophilic (blood eosinophil counts ≥150 cells/µL in admission; or ≥300 cells/µL in the previous year) patients with asthma suitable for both biologics were included in the study. Post-treatment changes in the asthma control test (ACT) score, number of attacks, forced expiratory volume in 1 second (FEV1), and eosinophil count were compared. The rates of any biological responder patient were compared according to whether they had high eosinophil counts (≥500 cells/µL vs <500 cells/µL). Total of 181 patients data were evaluated, of the 74 atopic and eosinophilic overlap patients included in the study, 56 were receiving omalizumab and 18 were receiving mepolizumab. When omalizumab and mepolizumab treatment efficacies were compared, there was no difference in terms of the reduction in attacks and improvement in ACT. The decrease in eosinophil levels in patients in the mepolizumab arm was significantly higher than that in patients in the omalizumab arm (46.3% vs 87.8%; P < .001). The improvement in FEV1 was greater with mepolizumab treatment, although the difference was not significant (215 mL vs 380 mL; P = .053). It has been shown that having high eosinophil counts does not affect the clinical and spirometric responder patient rates for either biological condition. The success of omalizumab and mepolizumab treatment is similar in patients with atopic and eosinophilic overlap with severe asthma. However, because the baseline patient inclusion criteria are not compatible, head-to-head studies comparing both biological agents are required.
Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Eosinofilia Pulmonar , Humanos , Omalizumab/uso terapêutico , Antiasmáticos/uso terapêutico , Fatores Biológicos/uso terapêutico , Estudos Retrospectivos , Estudos Transversais , Asma/induzido quimicamente , Eosinofilia Pulmonar/induzido quimicamente , Resultado do Tratamento , Produtos Biológicos/uso terapêuticoRESUMO
BACKGROUND: The efficacy of benralizumab has been broadly demonstrated in severe eosinophilic asthma (SEA), but only few real-life studies evaluated its long-term effects. Here we present novel data from the ANANKE study in which a large cohort of SEA patients was treated for up to 96 weeks. METHODS: ANANKE (NCT04272463) is an observational retrospective Italian study investigating the key characteristics of SEA patients (collected during the 12 months prior to benralizumab initiation) and the clinical outcomes during benralizumab treatment (annual exacerbation rate [AER], lung function, asthma control, OCS use, healthcare resource utilization). A post hoc analysis was also conducted in groups of patients based on history of previous biologic therapy (bio-experienced versus naïve patients). Analyses were descriptive only. RESULTS: Before benralizumab initiation, evaluable SEA patients (N = 162, 61.1% females, mean age 56.0 ± 12.7) showed a median blood eosinophil count (BEC) of 600 cells/mm3 (IQR: 430-890). Patients experienced frequent exacerbations (annualized exacerbation rate [AER]: 4.10, severe AER: 0.98), with impaired lung function and poor asthma control (median ACT score: 14) despite 25.3% reported oral corticosteroid (OCS) use. Nasal polyposis was present in 53.1% patients; 47.5% patients were atopic. After 96 weeks since the start of benralizumab, nearly 90% patients were still on treatment; benralizumab dramatically decreased exacerbations (AER: - 94.9%; severe AER: - 96.9%), improved respiratory parameters (median increase in pre-bronchodilator forced expiratory volume [pre-BD FEV1]: + 400 mL) and asthma control (median ACT score: 23) while eliminating OCS in 60% patients. Importantly, benralizumab effects were either maintained or progressively improved over time, accompanied by a nearly complete depletion of BEC. Benralizumab reduced AER both in naïve (any AER: - 95.9%; severe AER: - 97.5%) and bio-experienced patients (any AER: - 92.4%; severe AER: - 94.0%). CONCLUSIONS: Profound and sustained improvements in all asthma outcomes were observed with benralizumab. The correct identification of patients' eosinophilic-driven asthma phenotype was essential to ensure the achievement of such remarkable results. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04272463.
Assuntos
Antiasmáticos , Asma , Eosinofilia Pulmonar , Feminino , Masculino , Humanos , Antiasmáticos/efeitos adversos , Estudos Retrospectivos , Progressão da Doença , Método Duplo-Cego , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/induzido quimicamente , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/tratamento farmacológico , Eosinófilos , Corticosteroides/uso terapêuticoRESUMO
Cockroaches can cause allergic sensitization in humans via contact with their feces or frass. Antibiotics can affect concentration of major allergen and total bacteria production in German cockroaches (Blattella germanica). This study examined the ability of antibiotic-treated German cockroaches to induce allergic airway inflammation and the effect of antibiotics on their lipopolysaccharide and Bla g1, 2, and 5 expression levels. Specifically, we measured the ability of German cockroach extract (with or without prior antibiotic exposure) to induce allergic inflammation in human bronchial epithelial cells and a mouse model of asthma. Bacterial 16S rRNA and lipopolysaccharide levels were lower in ampicillin-treated cockroaches than in the control group. The Bla g1, Bla g2, and Bla g5 expression in ampicillin-treated cockroaches decreased at both the protein and RNA levels. In human bronchial epithelial cell lines BEAS-2B exposed to the ampicillin-treated extract, expression levels of interleukin-6 and interleukin-8 were lower than that in the control group. The total cell count and eosinophil count in bronchoalveolar lavage fluid was also lower in mice exposed to the ampicillin-treated extract than in those exposed to normal cockroach extract. Mouse lung histopathology showed reduced immune cell infiltration and mucus production in the ampicillin group. Our results showed that ampicillin treatment reduced the symbiont bacterial population and major allergen levels in German cockroaches, leading to reduced airway inflammation in mice. These results can facilitate the preparation of protein extracts for immunotherapy or diagnostics applications.
Assuntos
Asma , Blattellidae , Humanos , Camundongos , Animais , Lipopolissacarídeos , RNA Ribossômico 16S , Asma/induzido quimicamente , Pulmão , Inflamação/tratamento farmacológico , Alérgenos , Ampicilina/farmacologia , Antibacterianos/farmacologiaRESUMO
BACKGROUND AND OBJECTIVE: Asthma is a common chronic inflammatory disease of the airways with no known cure. Lipid mediators (LMs) are a kind of inflammatory signaling molecules which are believed to be involved in the development of asthma. Hyssopus cuspidatus Boriss. is a traditional Uyghur medicine, which is widely used in the treatment of asthma and other respiratory diseases. Extraction of Hyssopus cuspidatus Boriss. was reported to neutralize asthma symptoms. The purpose of the study was to investigate both the anti-inflammatory and immunoregulation properties of the Hyssopus cuspidatus Boriss. extract (SXCF) and its main active constituent, rosmarinic acid (RosA), in vivo. The effect of RosA, a major constituent of SXCF, was evaluated on an asthmatic model, with both anti-inflammatory and immunoregulation properties. MATERIALS AND METHODS: Anti-inflammatory effect of SXCF and RosA was assessed using OVA-induced asthma model mice by UPLC-MS/MS method. RESULTS: Overall, RosA played a critical role in anti-asthma treatment. In total, 90% of LMs species that were significantly regulated by SXCF were covered. On the most important LMs associated with asthma, RosA equivalent induced similar effects as SXCF did. It is believed that some constituents in SXCF could neutralize RosA excessive impacts on LMs.
Assuntos
Asma , Espectrometria de Massas em Tandem , Camundongos , Animais , Cromatografia Líquida , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/metabolismo , Anti-Inflamatórios/farmacologia , Hyssopus , Lipídeos/uso terapêutico , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , Ovalbumina/efeitos adversos , Citocinas/metabolismo , Líquido da Lavagem BroncoalveolarRESUMO
Purpose: To investigate the role of neferine in ovalbumin (OVA)-induced asthma, and to reveal the possible mechanism. Methods: In OVA-induced asthmatic mice, enzyme-linked-immunosorbent serologic assay was performed to evaluate the level of interleukin (IL)-4, IL-5, IL-13, immunoglobulin E (IgE) in serum and tumor necrosis factor-α (TNF-α), IL-6, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF). Eosinophil, neutrophil, and lymphocyte counts in BALF were calculated to assess inflammation. The pulmonary function was measured by airway resistance, peak expiratory flow (PEF) and forced expiratory volume/forced vital capacity (FEV0.4/FVC) ratio, and respiratory rate. Hematoxylin and eosin staining and Masson staining were used to evaluate lung injury. Further, Western blot analysis was conducted to detect phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 of mitogen-activated protein kinase (MAPK) signaling pathways. Results: Neferine, 20 mg/kg or 40 mg/kg, could significantly decrease the levels of IL-4, IL-5, IL-13, and IgE in OVA-induced serum, and that of TNF-α, IL-6, IL-1β, and MCP-1 in OVA-induced BALF. Moreover, neferine could significantly decline eosinophil, neutrophil, and lymphocyte counts in BALF. Neferine contributed to improve OVA-induced airway resistance, promoted the value of PEF and FEV0.4/FVC ratio, and recovered the respiratory rate. It also reduced mucus secretion, distribution of inflammatory and goblet cells around bronchi, and attenuated collagen deposition in lung tissues. Furthermore, neferine reduced the phosphorylation of p38, JNK, and ERK to inhibit MAPK signaling pathways. Conclusion: Neferine relieves asthma-induced inflammatory reaction, airway resistance, and lung injury by inhibiting MAPK signaling pathways. This could serve neferine as a novel therapeutic candidate for treating asthma (AU)
Assuntos
Animais , Feminino , Camundongos , Ovalbumina/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Ensaio de Imunoadsorção Enzimática , Western Blotting , Transdução de SinaisRESUMO
BACKGROUND: Ambient air pollution exposure has been associated with childhood asthma, but previous studies have primarily focused on prevalence of asthma and asthma-related outcomes and urban traffic-related exposures. OBJECTIVE: We examined nationwide associations between pre- and postnatal exposure to ambient air pollution components and asthma incidence in children age 0-19 y. METHODS: Asthma incidence was identified from hospital admission, emergency room, and outpatient contacts among all live-born singletons born in Denmark between 1998 and 2016. We linked registry data with monthly mean concentrations of particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5) and PM with aerodynamic diameter ≤10µm (PM10), nitrogen dioxide (NO2), nitrogen oxides, elemental carbon, and organic carbon (OC), sulfur dioxide, ozone, sulfate, nitrate, ammonium, secondary organic aerosols, and sea salt. Associations were estimated with Cox proportional hazard models using fixed prenatal exposure means and time-varying postnatal exposures. RESULTS: Of the 1,060,154 children included, 6.1% had asthma during the mean follow-up period of 8.8 y. The risk of asthma increased with increasing prenatal exposure to all pollutants except for O3 and sea salt. We also observed increased risk after restriction to asthma after age 4 y, after additional adjustment for area-specific socioeconomic status, and for postnatal exposure to most pollutants. The hazard ratio (HR) associated with an interquartile range increase of 2.4 and 8.7 µg/m3 in prenatal exposure was 1.06 [95% confidence interval (CI): 1.04, 1.08] for PM2.5 and 1.04 (95% CI: 1.02, 1.05) for NO2, respectively. This association with PM2.5 was stable after adjustment for NO2, whereas it attenuated for NO2 to 1.01 (95% CI: 0.99, 1.03) after adjustment for PM2.5. For a 0.5-µg/m3 increase in prenatal OC exposure, for which biomass is an important source, the HR was 1.08 (95% CI: 1.06, 1.10), irrespective of adjustment for PM2.5. DISCUSSION: These findings suggest that early-life exposure to ambient air pollution from multiple sources contributes to asthma development. https://doi.org/10.1289/EHP11539.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Asma , Poluentes Ambientais , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Feminino , Humanos , Criança , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Estudos de Coortes , Poluentes Atmosféricos/análise , Incidência , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Exposição Ambiental/efeitos adversos , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Asma/induzido quimicamente , Asma/epidemiologia , Material Particulado/análise , Dióxido de Nitrogênio/análise , Carbono , Dinamarca/epidemiologiaRESUMO
Recent experimental and observational research has suggested that childhood allergic asthma and other conditions may be the result of prenatal exposure to environmental contaminants, such as di-(2-ethylhexyl) phthalate (DEHP). In a previous epidemiological study, we found that ancestral exposure (F0 generation) to endocrine disruptors or the common plasticizer DEHP promoted allergic airway inflammation via transgenerational transmission in mice from generation F1 to F4. In the current study, we employed a MethylationEPIC Beadchip microarray to examine global DNA methylation in the human placenta as a function of maternal exposure to DEHP during pregnancy. Interestingly, global DNA hypomethylation was observed in placental DNA following exposure to DEHP at high concentrations. Bioinformatic analysis confirmed that DNA methylation affected genes related to neurological disorders, such as autism and dementia. These results suggest that maternal exposure to DEHP may predispose offspring to neurological diseases. Given the small sample size in this study, the potential role of DNA methylation as a biomarker to assess the risk of these diseases deserves further investigation.
Assuntos
Asma , Dietilexilftalato , Disruptores Endócrinos , Doenças do Sistema Nervoso , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Animais , Feminino , Camundongos , Humanos , Criança , Dietilexilftalato/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Placenta , Exposição Materna/efeitos adversos , Epigênese Genética , Asma/induzido quimicamente , Asma/epidemiologia , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/genéticaRESUMO
Empagliflozin, a selective inhibitor of Na+-glucose cotransporter-2, has been reported to exert anti-inflammatory and anti-fibrotic effects in addition to autophagy modulation. Addressing the role of autophagy in allergic asthma revealed controversial results. The potential effect of empagliflozin treatment on airway inflammation and remodelling as well as autophagy modulation in a murine model of allergic asthma was investigated. Over a 7-week period, male BALB/c mice were sensitized and challenged by intraperitoneal injection and inhalation of ovalbumin, respectively. Animals were treated with empagliflozin (10 mg/kg; orally) and/or rapamycin (an autophagy inducer; 4 mg/kg; intraperitoneally) before every challenge. Methacholine-induced airway hyperresponsiveness was evaluated one day after the last challenge. After euthanasia, serum, bronchoalveolar lavage fluid, and lung tissues were collected for biochemical, histopathological, and immunohistochemical assessment. Results revealed that empagliflozin decreased airway hyperresponsiveness, serum ovalbumin-specific immunoglobulin E, and bronchoalveolar lavage total and differential leukocytic counts. Levels of inflammatory and profibrotic cytokines (IL-4, IL-5, IL-13, IL-17, and transforming growth factor-ß1) were all inhibited. Moreover, empagliflozin preserved pulmonary microscopic architecture and alleviated bronchiolar epithelial thickening, goblet cell hyperplasia, fibrosis and smooth muscle hypertrophy. These effects were associated with inhibition of ovalbumin-activated autophagic flux, as demonstrated by decreased LC3B expression and LC3BII/I ratio, as well as increased P62 expression. However, the therapeutic potential of empagliflozin was inhibited when rapamycin was co-administered. In conclusion, this study demonstrates that empagliflozin has immunomodulatory, anti-inflammatory, and anti-remodelling properties in ovalbumin-induced allergic asthma and suggests that autophagic flux inhibition may play a role in empagliflozin's anti-asthmatic effects.
Assuntos
Asma , Hipersensibilidade Respiratória , Masculino , Animais , Camundongos , Ovalbumina , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/metabolismo , Pulmão/patologia , Líquido da Lavagem Broncoalveolar/química , Hipersensibilidade Respiratória/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Autofagia , Camundongos Endogâmicos BALB C , Modelos Animais de DoençasRESUMO
This study aimed to investigate the effects of sulfur dioxide (SO2) derivatives on asthma induced by ovalbumin (OVA). Sprague Dawley rats were sensitized to and challenged with OVA and SO2 derivatives (NaHSO3 and Na2SO3, 1:3 M/M) to establish 28-day (short-term) and 42-day (long-term) asthma models. Exposure to SO2 derivatives aggravated asthma and hence, promoted lung injury in OVA-induced asthma. In addition, it upregulated the protein expression of TRPV1 and downregulated the expression of tight junctions (TJs). These changes were dose-dependent and were more pronounced in the presence of a high concentration of SO2 derivatives. In vitro, SO2 derivatives also increased the calcium influx and TRPV1 protein expression, and decreased TJ expression. Besides, no significant difference in the TJ expression was found between the WT and TRPV1-/- mice. The underlying mechanism might be related to regulating the effects of TRPV1 and TJs.
Assuntos
Asma , Dióxido de Enxofre , Ratos , Camundongos , Animais , Dióxido de Enxofre/efeitos adversos , Dióxido de Enxofre/metabolismo , Ovalbumina/efeitos adversos , Junções Íntimas , Ratos Sprague-Dawley , Asma/induzido quimicamente , Asma/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Canais de Cátion TRPV/genéticaRESUMO
Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust particles (DEP) is implicated in both exacerbation and development of asthma. Since exposure to DEP is associated with a neutrophilic component, we aimed to investigate how exposure to the combination of allergens and DEP modulates neutrophilic responses. Human bronchial epithelial cells (HBEC) were exposed to house dust mite (HDM), DEP or HDM + DEP in vitro to determine the expression of neutrophil-recruiting chemokines. Female (C57BL/6 J) mice were intranasally instilled with saline, DEP, HDM or combined HDM + DEP for 3 weeks (subacute) or 6 weeks (chronic). The neutrophilic responses were determined in lung tissue and bronchoalveolar lavage fluid (BALF). Simultaneous exposure to HDM + DEP resulted in increased CXCL1 and CXCL8 mRNA expression by HBEC in vitro. In mice, subacute exposure to HDM + DEP induced a strong mixed eosinophilic/neutrophilic inflammation in BALF and lung and was associated with higher expression of neutrophil-attracting chemokines and NET formation compared to the sole exposures. After chronic HDM + DEP exposure, a similar neutrophilic response was observed, however the NET formation was less pronounced. Interestingly, the increase of BALF eosinophils was also significantly attenuated after chronic HDM + DEP exposure compared to the subacute exposure. Subacute and chronic HDM + DEP exposure induced goblet cell hyperplasia and airway hyperresponsiveness. Our data suggest a role for neutrophils and NETs in pollutant-aggravated eosinophilic allergic asthma. Moreover, subacute exposure to HDM + DEP induces a mixed eosinophilic/neutrophilic response whereas upon chronic HDM + DEP exposure there is a shift in inflammatory response with a more prominent neutrophilic component.
Assuntos
Asma , Poluentes Ambientais , Hipersensibilidade , Feminino , Humanos , Camundongos , Animais , Poluentes Ambientais/metabolismo , Camundongos Endogâmicos C57BL , Asma/induzido quimicamente , Pulmão/metabolismo , Modelos Animais de Doenças , Alérgenos/toxicidade , PyroglyphidaeRESUMO
Exposure to formaldehyde (FA) has been indicated to be positively correlated with increased incidence of allergic asthma in many epidemiological and experimental studies. However, few studies have ever addressed the molecular basis of the correlation. In the present study, it was found that inhaling 2.0 mg/m3 FA for 2 weeks could exacerbate the pulmonary inflammation and mucus over-accumulation in OVA-induced murine asthmatic model. The pro-inflammatory cytokines, such as IL-1ß, TNF-α, IL-6 and IL-8, were increased in lung and serum of FA-exposed asthmatic mice. The contribution of HIF-1α signaling in FA-exacerbated allergic asthma was confirmed by bioinformatic analysis. HIF-1α and its downstream proteins, which are known as mediators of glycolysis, were found to be upregulated by 50 µM FA, and the FA-enhanced of glycolysis was reversed by inhibition of HIF-1α with PX-478 in vitro and YC-1 in vivo. Furthermore, it was confirmed that inhibition of HIF-1α signaling could restrain the macrophagic inflammatory responses and asthma exacerbation induced by FA. Collectively, these results revealed that FA could exacerbate asthma through the potentiation of HIF-1α-mediated inflammatory responses in macrophages, which also indicated the universal roles of FA-triggered macrophage metabolic and functional alterations in inflammatory or allergic diseases.
Assuntos
Asma , Hipersensibilidade , Camundongos , Animais , Macrófagos Alveolares/metabolismo , Asma/induzido quimicamente , Asma/metabolismo , Pulmão/metabolismo , Formaldeído/toxicidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
Background: Anti-type 2 inflammation therapy has been proposed as a treatment strategy for eosinophil-associated chronic airway disorders that could reduce exacerbations and improve lung function. We performed a meta-analysis of randomized controlled trials to assess the effectiveness of type 2 monoclonal antibodies (anti-T2s) for eosinophil-associated chronic airway disorders. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched from their inception to 21 August 2022. Randomized clinical trials evaluating the effectiveness of anti-T2s versus placebo in the treatment of chronic airway diseases were selected. The outcomes were exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline. The Cochrane Risk of Bias Assessment Tool 1.0 was used to evaluate the risk of bias, and the random-effects or fixed-effect model were used to pool the data. Results: Thirty-eight articles concerning forty-one randomized clinical trials with 17,115 patients were included. Compared with placebo, anti-T2s therapy yielded a significant reduction in exacerbation rate in COPD and asthma (Rate Ratio (RR)=0.89, 95%CI, 0.83-0.95, I2 = 29.4%; RR= 0.59, 95%CI, 0.52-0.68, I2 = 83.9%, respectively) and improvement in FEV1 in asthma (Standard Mean Difference (SMD)=0.09, 95%CI, 0.08-0.11, I2 = 42.6%). Anti-T2s therapy had no effect on FEV1 improvement in COPD (SMD=0.05, 95%CI, -0.01-0.10, I2 = 69.8%). Conclusion: Despite inconsistent findings across trials, anti-T2s had a positive overall impact on patients' exacerbation rate in asthma and COPD and FEV1 in asthma. Anti-T2s may be effective in treating chronic airway illnesses related to eosinophils. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022362280.
Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Eosinófilos , Anticorpos Monoclonais/uso terapêutico , Progressão da Doença , Asma/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Crônica , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Although the classic form of asthma is characterized by chronic pneumonitis with eosinophil infiltration and steroid responsivity, asthma has multifactorial pathogenesis and various clinical phenotypes. Previous studies strongly suggested that chemical exposure could influence the severity and course of asthma and reduce its steroid responsiveness. Cypermethrin (CYP), a common pesticide used in agriculture, was investigated for the possible aggravation of the ovalbumin (OVA)-induced allergic pneumonitis and the possible induction of steroid resistance in rats. Additionally, it was investigated whether pirfenidone (PFD) could substitute dexamethasone, as an alternative treatment option, for the induced steroid resistance. Fifty-six male Wistar albino rats were randomly divided into seven groups: control, PFD alone, allergic pneumonitis, CYP alone, allergic pneumonitis/CYP-exposed, allergic pneumonitis/CYP/dexamethasone (Dex), and allergic pneumonitis/CYP/PFD-treated groups. Allergic pneumonitis was induced by three intraperitoneal OVA injections administered once a week, followed by an intranasal OVA instillation challenge. CYP (25 mg/kg/d), Dex (1 mg/kg/d), and PFD (100 mg/kg/d) were administered orally from day 15 to the end of the experiment. Bronchoalveolar lavage fluid (BALF) was analyzed for cytokine levels. Hematoxylin and eosin (H&E) and periodic acid Schiff (PAS)-stained lung sections were prepared. Immunohistochemical identification of p38 MAPK and lung macrophages was performed. The inflammatory/oxidative status of the lung and PCR-quantification of the STAT6, p38 MAPK, MUC5AC, and IL-13 genes were carried out. The allergic pneumonitis-only group showed eosinophil-mediated inflammation (p < 0.05). Further CYP exposure aggravated lung inflammation and showed steroid-resistant changes, p38 activation, neutrophil-mediated, M1 macrophage-related inflammation (p < 0.05). All changes were reversed (p < 0.05) by PFD, meanwhile not by dexamethasone treatment. Pirfenidone could replace dexamethasone treatment in the current rat model of CYP-induced severe steroid-resistant asthma via inhibiting the M1 macrophage differentiation through modulation of the STAT6/p38 MAPK pathway.
Assuntos
Alveolite Alérgica Extrínseca , Asma , Pneumonia , Animais , Ratos , Masculino , Ovalbumina/efeitos adversos , Ratos Wistar , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/genética , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Inflamação , Macrófagos/metabolismo , Dexametasona/efeitos adversos , Fenótipo , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Dibutyl phthalate (DBP), used as a plasticizer, is of wide concern as an environmental pollutant since it has certain immunotoxicity. Although there is growing evidence supporting a link between DBP exposure and allergic airway inflammation, there is less information concerned with whether the ferroptosis pathway is involved in DBP-aggravated allergic asthma in ovalbumin (OVA)-sensitized mice. This study aimed to investigate the role and underlying mechanisms of ferroptosis in DBP-exposed allergic asthmatic mice. Balb/c mice were orally exposed to 40 mg/kg-1 DBP for 28 days, followed by sensitization with OVA and seven consecutive challenges with nebulized OVA. We analyzed airway hyperresponsiveness (AHR), immunoglobulins, inflammation and pulmonary histopathology, to investigate whether DBP exacerbates allergic asthma in OVA-induced mice. We also measured the biomarkers of ferroptosis (Fe2+, GPX4, PTGS2), proteins related to the ferroptosis pathway (VEGF, IL-33, HMGB1, SLC7A11, ALOX15, PEBP1), and indices of lipid peroxidation (ROS, Lipid ROS, GSH, MDA, 4-HNE), to explore the role of ferroptosis in DBP+OVA mice. Finally, we used ferrostatin-1 (Fer-1) as an antagonist against the harmful effects of DBP. The results showed that, DBP+OVA mice had a significant increase in AHR, airway wall remodeling and airway inflammation. Further, we showed that DBP aggravated allergic asthma via ferroptosis and lipid peroxidation, and that Fer-1 inhibited ferroptosis and alleviated the pulmonary toxicity of DBP. These results suggest that ferroptosis participates in the exacerbation of allergic asthma resulting from oral exposure to DBP, highlighting a novel pathway for the connection between DBP and allergic asthma.
Assuntos
Asma , Ferroptose , Hipersensibilidade , Animais , Camundongos , Ovalbumina/efeitos adversos , Dibutilftalato , Espécies Reativas de Oxigênio , Asma/induzido quimicamente , Pulmão , Inflamação , Camundongos Endogâmicos BALB CRESUMO
Polysaccharides, as one of the main types of bioactive components of Cordyceps militaris, have anti-allergic asthma effects. Herein, an ovalbumin-induced allergic asthma mouse model was established to assess the potential mechanisms of the separated and purified Cordyceps militaris polysaccharide (CMP). CMP is an α-pyranose with a molecular weight of 15.94 kDa that consists of Glc, Man, Gal, Xyl, Ara and GlcA in a molar ratio of 81.25:21.96:13.88:3.92:3.58:1.00. CMP improved inflammatory cytokine levels, alleviated the histopathological changes in the lung and intestinal tissues, regulated the expression of mRNA and proteins related to oxidative stress and inflammatory pathways, reversed gut dysbiosis at the phylum and family levels and improved microbiota function in allergic asthma mice. Moreover, it was found that the levels of inflammatory cytokines in lung tissue of mice were significantly correlated with some intestinal microbial communities. Overall, CMP improved oxidative stress and the inflammatory response in allergic asthma mice by regulating the Nrf2/HO-1 and NF-κB signaling pathways, which may be closely correlation with maintaining the stability of the gut microbiota.
Assuntos
Asma , Cordyceps , Microbioma Gastrointestinal , Camundongos , Animais , NF-kappa B/metabolismo , Ovalbumina , Cordyceps/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Asma/induzido quimicamente , Asma/tratamento farmacológico , Transdução de Sinais , Citocinas , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêuticoRESUMO
Particulate matter in the air exacerbates airway inflammation (AI) in asthma; moreover, prenatal exposure to concentrated urban air particles (CAPs) and diesel exhaust particles (DEPs) predisposes the offspring to asthma and worsens the resolution of AI in response to allergens. We previously tested the hypothesis that such exposure impairs the pathways of specialized proresolving mediators that are critical for resolution and found declined Lipoxin A4 (LxA4) and Resolvin E2 (RvE2) levels in the "at-risk" pups of exposed mothers. Here, we hypothesized that supplementation with synthetic LxA4 or RvE2 via the airway can ameliorate AI after allergen exposure, which has not been tested in models with environmental toxicant triggers. BALB/c newborns with an asthma predisposition resultant from prenatal exposure to CAPs and DEPs were treated once daily for 3 days with 750 ng/mouse of LxA4 or 300 ng/mouse of RvE2 through intranasal instillation, and they were tested with the intentionally low-dose ovalbumin protocol that elicits asthma in the offspring of particle-exposed mothers but not control mothers, mimicking the enigmatic maternal transmission of asthma seen in humans. LxA4 and RvE2 ameliorated the asthma phenotype and improved AI resolution, which was seen as declining airway eosinophilia, lung tissue infiltration, and proallergic cytokine levels.
Assuntos
Asma , Efeitos Tardios da Exposição Pré-Natal , Recém-Nascido , Humanos , Gravidez , Feminino , Camundongos , Animais , Exposição Materna/efeitos adversos , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/genética , Inflamação , Emissões de Veículos/toxicidadeRESUMO
The airway epithelial barrier dysfunction plays a crucial role in pathogenesis of asthma and causes the amplification of downstream inflammatory signal pathway. S100 calcium binding protein A4 (S100A4), which promotes metastasis, have recently been discovered as an effective inflammatory factor and elevated in bronchoalveolar lavage fluid in asthmatic mice. Vascular endothelial growth factor-A (VEGFA), is considered as vital regulator in vascular physiological activities. Here, we explored the probably function of S100A4 and VEGFA in asthma model dealt with house dust mite (HDM) extracts. Our results showed that secreted S100A4 caused epithelial barrier dysfunction, airway inflammation and the release of T-helper 2 cytokines through the activation of VEGFA/VEGFR2 signaling pathway, which could be partial reversed by S100A4 polyclonal antibody, niclosamide and S100A4 knockdown, representing a potential therapeutic target for airway epithelial barrier dysfunction in asthma.
Assuntos
Asma , Pyroglyphidae , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular , Asma/induzido quimicamente , Dermatophagoides pteronyssinus , Citocinas , Modelos Animais de DoençasRESUMO
Asthma often presents with a daily rhythm; however, the underlying mechanisms remain unclear. Circadian rhythm genes have been proposed to regulate inflammation and mucin expression. Here, ovalbumin (OVA)-induced mice and serum shock human bronchial epidermal cells (16HBE) were used in in vivo and in vitro models, respectively. We constructed a brain and muscle ARNT-like 1 (BMAL1) knockdown 16HBE cell line to analyze the effects of rhythmic fluctuations on mucin expression. Serum immunoglobulin E (IgE) and circadian rhythm genes in asthmatic mice showed rhythmic fluctuation amplitude. Mucin (MUC) 1 and MUC5AC expression was increased in the lung tissue of the asthmatic mice. MUC1 expression was negatively correlated with that of the circadian rhythm genes, particularly BMAL1 (r = -0.546, P = 0.006). There was also a negative correlation between BMAL1 and MUC1 expression (r = -0.507, P = 0.002) in the serum shock 16HBE cells. BMAL1 knockdown negated the rhythmic fluctuation amplitude of MUC1 expression and upregulated MUC1 expression in the 16HBE cells. These results indicate that the key circadian rhythm gene, BMAL1, causes periodic changes in airway MUC1 expression in OVA-induced asthmatic mice. Targeting BMAL1 to regulate periodic changes in MUC1 expression may, therefore, improve asthma treatments.
Assuntos
Fatores de Transcrição ARNTL , Asma , Animais , Humanos , Camundongos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Asma/induzido quimicamente , Asma/genética , Asma/metabolismo , Encéfalo/metabolismo , Mucina-1/genética , Mucina-1/metabolismo , Mucinas/metabolismo , Músculos/metabolismo , Ovalbumina/metabolismoRESUMO
AIMS: Overproduction of pro-inflammatory cytokines and its-mediated immune cell infiltration play a crucial role in asthma progression. In this study, we investigated the role of ginsenoside Rh1 (Rh1) in ovalbumin (OVA)/lipopolysaccharide (LPS)-induced allergic asthma both in vitro and in vivo. MATERIALS AND MAIN METHODS: The phorbol ester (PMA) and LPS were used to induce inflammation in lung airway cells and macrophage activation, respectively. Western blotting, quantitative reverse transcription-PCR, and immunofluorescence (IF) assays were performed to elucidate the underlying molecular mechanisms. To evaluating the effects of Rh1 in vivo, OVA and LPS were used to establish allergic asthma models. KEY FINDINGS: Rh1 significantly suppressed PMA-induced lung inflammation and macrophage activation by suppressing pro-inflammatory cytokines (TNF-α, IL-1ß, MCP-1), ICMA-1, and matrix metallopeptidase 9 (MMP9) in A549 cells. Rh1 abolished the PMA-induced inflammation by suppressing MAPK, Akt, and NF-κB p65. Pretreatment with Rh1 blocked PMA-mediated translocation of NF-κB, a key marker of pro-inflammatory cytokine release, into the nucleus. Similar to PMA-induced lung inflammation, Rh1 suppressed LPS-induced macrophage activation by suppressing NF-κB p65 activation and inducible nitric oxide synthase protein and mRNA expression. Consistent with in vitro data, LPS injection enhanced the number of immune cells induced by OVA in bronchoalveolar lavage fluid, whereas 20 mg/kg Rh1 significantly decreased OVA/LPS-mediated immune cell induction. In addition, Rh1 inhibited eosinophil, macrophage, and neutrophil maturation through by IL-4 and OVA-specific IgE production. SIGNIFICANCE: Rh1 protects against OVA/LPS-induced allergic asthma by suppressing immune cell infiltration by blocking the activation of MAPK, Akt, and NF-κB signaling pathways.
Assuntos
Asma , Pneumonia , Humanos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lipopolissacarídeos/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Transdução de Sinais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/metabolismo , Citocinas/metabolismo , Pneumonia/metabolismo , Líquido da Lavagem Broncoalveolar , OvalbuminaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Shaoyao-Gancao Tang (SGT) is a traditional Chinese medicine formulation. It has been used to treat kinds of pain and to alleviate asthma in clinic. However, the mechanism of action is not known. AIM OF THE STUDY: To investigate the anti-asthma effect of SGT involving modulation of the T-helper type 1 (Th1) Th1/Th2 ratio in the gut-lung axis and alteration of the gut microbiota (GM) in rats with ovalbumin (OVA)-induced asthma. MATERIALS AND METHODS: The main constituents of SGT were analyzed by high-performance liquid chromatography (HPLC). A model of asthma was established in rats by OVA-induced allergen challenge. Rats suffering from asthma (RSAs) were treated with SGT (2.5, 5.0 and 10.0 g/kg), dexamethasone (1 mg/kg) or physiologic saline for 4 weeks. The level of immunoglobulin (Ig)E in bronchoalveolar lavage fluid (BALF) and serum was determined by enzyme-linked immunosorbent assay. Histology of lung and colon tissues was investigated using staining (hematoxylin and eosin and periodic acid-Schiff). The Th1/Th2 ratio and levels of cytokines (interferon (IFN)-γ and interleukin (IL)-4) in the lung and colon were detected by immunohistochemistry. The GM in fresh feces was analyzed by 16 S rRNA gene sequencing. RESULTS: Twelve main constituents (gallic acid, albiflorin, paeoniflorin, liquiritin apioside, liquiritin, benzoic acid, isoliquiritin apioside, isoliquiritin, liquiritigenin, glycyrrhizic acid, isoliquiritigenin and glycyrrhetinic acid) of SGT were simultaneously determined by HPLC. SGT treatment (5.0 and 10.0 g/kg) was found to reduce the IgE level (a vital marker of hyper-responsiveness) in BALF and serum, improve typical morphological changes (inflammatory-cell infiltration and goblet cell metaplasia) in the lung and colon, alleviate airway remodeling (including bronchiostenosis and basement membrane-thickening) in the lung, significantly decrease the IL-4 level and increase the IFN-γ level in the lung and colon, which led to restoration of the IFN-γ/IL-4 ratio. The dysbiosis and dysfunction of GM in RSAs were modulated by SGT. The abundance of bacteria of the genera Ethanoligenens and Harryflintia was increased in RSAs and was decreased upon SGT treatment. The abundance of Family_XIII_AD3011_group was decreased in RSAs and increased upon SGT treatment. Moreover, SGT therapy increased the abundance of bacteria of the genera Ruminococcaceae_UCG-005 and Candidatus_Sacchrimonas, and decreased that of Ruminococcus_2 and Alistipes. CONCLUSIONS: SGT ameliorated rats with OVA-induced asthma via regulation of the Th1/Th2 ratio in the lung and gut, and modulated the GM.
