RESUMO
Lung inflammation and alveolar enlargement are the major pathological conditions of chronic obstructive pulmonary disease (COPD) patients. Rice bran oil (RBO), a natural anti-inflammatory and antioxidative agent, has been used for therapeutic purposes in several inflammatory diseases. This study aimed to investigate the anti-inflammatory and antioxidative effect of RBO on a cigarette smoke extract (CSE)-induced emphysema model in mice. The results indicated that CSE significantly induced airspace enlargement in mouse lung. Increased inflammatory cells, macrophage, and TNF-alpha levels in bronchoalveolar lavage fluid (BALF) were noticed in CSE-treated mice. RBO (low and high dose)-supplemented mice showed decreased total BALF inflammatory cell, macrophage, and neutrophil numbers and TNF-alpha levels (p < 0.05). Additionally, the administration of RBO decreased the mean linear alveolar intercept (MLI) in the CSE-treated group. Additionally, RBO treatment significantly increased the total antioxidant capacity in both mouse BALF and serum. However, RBO did not have an effect on the malondialdehyde (MDA) level. These findings suggested that RBO treatment ameliorates lung inflammation in a CSE-induced emphysema mice model through anti-inflammatory and antioxidant pathways. Therefore, the supplementation of RBO could be a new potential therapeutic to relieve the severity of COPD.
Assuntos
Fumar Cigarros , Enfisema , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Camundongos , Animais , Antioxidantes/metabolismo , Pulmão/patologia , Óleo de Farelo de Arroz/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fumar Cigarros/efeitos adversos , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Anti-Inflamatórios/uso terapêutico , Pneumonia/tratamento farmacológico , Líquido da Lavagem Broncoalveolar , Enfisema/induzido quimicamente , Enfisema/tratamento farmacológico , Produtos do TabacoRESUMO
The activity of PP2A (protein phosphatase 2A), a serine-threonine phosphatase, is reduced by chronic cigarette smoke (SM) exposure and α-1 antitrypsin (AAT) deficiency, and chemical activation of PP2A reduces the loss of lung function in SM-exposed mice. However, the previously studied PP2A-activator tricyclic sulfonamide compound DBK-1154 has low stability to oxidative metabolism, resulting in fast clearance and low systemic exposure. Here we compare the utility of a new more stable PP2A activator, ATUX-792, versus DBK-1154 for the treatment of SM-induced emphysema. ATUX-792 was also tested in human bronchial epithelial cells and a mouse model of AAT deficiency, Serpina1a-e-knockout mice. Human bronchial epithelial cells were treated with ATUX-792 or DBK-1154, and cell viability, PP2A activity, and MAP (mitogen-activated protein) kinase phosphorylation status were examined. Wild-type mice received vehicle, DBK-1154, or ATUX-792 orally in the last 2 months of 4 months of SM exposure, and 8-month-old Serpina1a-e-knockout mice received ATUX-792 daily for 4 months. Forced oscillation and expiratory measurements and histology analysis were performed. Treatment with ATUX-792 or DBK-1154 resulted in PP2A activation, reduced MAP kinase phosphorylation, immune cell infiltration, reduced airspace enlargements, and preserved lung function. Using protein arrays and multiplex assays, PP2A activation was observed to reduce AAT-deficient and SM-induced release of CXCL5, CCL17, and CXCL16 into the airways, which coincided with reduced neutrophil lung infiltration. Our study indicates that suppression of the PP2A activity in two models of emphysema could be restored by next-generation PP2A activators to impact lung function.
Assuntos
Enfisema , Enfisema Pulmonar , Humanos , Animais , Camundongos , Lactente , Proteína Fosfatase 2/metabolismo , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/metabolismo , Pulmão/metabolismo , Enfisema/tratamento farmacológico , Enfisema/metabolismo , Camundongos KnockoutRESUMO
Human neutrophil elastase (HNE) is an enzyme that plays a key role in the body's inflammatory response. It has been linked to several diseases such as chronic obstructive pulmonary disease (COPD), emphysema, and cystic fibrosis. As potential treatments for these diseases, HNE inhibitors are of great interest. Metabolites derived from plants, particularly terpenoids such as ß-caryophyllene found in black pepper and other plants, and geraniol present in several essential oils, are recognized as significant sources of inhibitors for HNE. Because of their ability to inhibit HNE, terpenoids are considered promising candidates for developing novel therapies to treat inflammatory conditions such as COPD and emphysema. Furthermore, nature can serve as an excellent designer, and it may offer a safer drug candidate for inhibiting HNE production and activity in the future. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were searched to get relevant and up-to-date literature on terpenoids as human neutrophil elastase inhibitors. This review focuses on the isolation, chemical diversity, and inhibition of human neutrophil elastase (HNE) of various terpenoids reported from natural sources up to 2022. A total of 251 compounds from various terpenoids classes have been reported. Further, it also provides a summary of HNE inhibitors and includes a thorough discussion on the structure-activity relationship.
Assuntos
Enfisema , Doença Pulmonar Obstrutiva Crônica , Humanos , Elastase de Leucócito/metabolismo , Elastase de Leucócito/uso terapêutico , Terpenos/farmacologia , Terpenos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Enfisema/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
Emphysema is a chronic obstructive lung disease characterized by inflammation and enlargement of the air spaces. Regorafenib, a potential senomorphic drug, exhibited a therapeutic effect in porcine pancreatic elastase (PPE)-induced emphysema in mice. In the current study we examined the preventive role of regorafenib in development of emphysema. Lung function tests and morphometry showed that oral administration of regorafenib (5 mg/kg/day) for seven days after instillation of PPE resulted in attenuation of emphysema. Mechanistically, regorafenib reduced the recruitment of inflammatory cells, particularly macrophages and neutrophils, in bronchoalveolar lavage fluid. In agreement with these findings, measurements using a cytokine array and ELISA showed that expression of inflammatory mediators including interleukin (IL)-1ß, IL-6, and CXCL1/KC, and tissue inhibitor of matrix metalloprotease-1 (TIMP-1), was downregulated. The results of immunohistochemical analysis confirmed that expression of IL-6, CXCL1/KC, and TIMP-1 was reduced in the lung parenchyma. Collectively, the results support the preventive role of regorafenib in development of emphysema in mice and provide mechanistic insights into prevention strategies. [BMB Reports 2023; 56(8): 439-444].
Assuntos
Enfisema , Enfisema Pulmonar , Animais , Camundongos , Modelos Animais de Doenças , Enfisema/tratamento farmacológico , Interleucina-6 , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Elastase Pancreática , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/metabolismo , Suínos , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Inibidor Tecidual de Metaloproteinase-1/uso terapêuticoRESUMO
Human neutrophil elastase (HNE) plays a pivotal role in innate immunity, inflammation, and tissue remodeling. Aberrant proteolytic activity of HNE contributes to organ destruction in various chronic inflammatory diseases including emphysema, asthma, and cystic fibrosis. Therefore, elastase inhibitors could alleviate the progression of these disorders. Here, we used the systematic evolution of ligands by exponential enrichment to develop ssDNA aptamers that specifically target HNE. We determined the specificity of the designed inhibitors and their inhibitory efficacy against HNE using biochemical and in vitro methods, including an assay of neutrophil activity. Our aptamers inhibit the elastinolytic activity of HNE with nanomolar potency and are highly specific for HNE and do not target other tested human proteases. As such, this study provides lead compounds suitable for the evaluation of their tissue-protective potential in animal models.
Assuntos
Aptâmeros de Nucleotídeos , Elastase de Leucócito , Inibidores de Serina Proteinase , Humanos , Fibrose Cística/tratamento farmacológico , Enfisema/tratamento farmacológico , Elastase de Leucócito/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/uso terapêutico , Aptâmeros de Nucleotídeos/síntese química , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/uso terapêutico , Sensibilidade e Especificidade , Ativação Enzimática/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Células CultivadasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Oleo-gum resin of Commiphora wightii (Arnott) Bhandari of family Burseraceae, commonly known as 'guggul', is a well known Ayurvedic drug used traditionally to treat various disorders including respiratory ailments. However, role of C. wightii in chronic obstructive pulmonary disease (COPD) is not known. AIM: The present work was designed to investigate the protective potential of standardized C. wightii extract/and its fractions against elastase-induced COPD-linked lung inflammation and to identify key bioactive constituent(s). MATERIAL AND METHODS: C. wightii oleo-gum resin extract was prepared using Soxhlet extraction technique and the resultant extract was standardized on basis of guggulsterone content using HPLC. The extract was partitioned by different solvents in increasing order of polarity. Standardized extract/its partitioned fractions were orally administered to male BALB/c mice 1 h prior to intra-tracheal instillation of elastase (1U/mouse). Anti-inflammatory effect was evaluated by analyzing inflammatory cells and myeloperoxidase activity in lungs. The various fraction(s) were subjected to column chromatography to isolate bioactive compound. Isolated compound was identified using 1H and 13C-NMR and analyzed for assessment of several inflammatory mediators using techniques like ELISA, PCR, and gelatin zymography. RESULTS: C. wightii extract attenuated elastase-induced lung inflammation in dose-dependent manner and Ethyl acetate fraction (EAF) provided maximum protection. EAF was subjected to column chromatography followed by assessment of bioactivity of each sub-fraction, ultimately leading towards isolation of two compounds i.e. C1 and C2. C1 seems to be the key active principle of C. wightii, as it displayed significant anti-inflammatory activity against elastase induced lung inflammation while C2 largely remains ineffective. C1 was identified as mixture of E- and Z-guggulsterone (GS). Reduction in the elastase induced lung inflammation by GS was associated with downregulation of expression of several COPD linked pro-inflammatory factors such as IL-6/TNF-α/IL-1ß/KC/MIP-2/MCP-1/G-CSF as well as normalization of redox imbalance as indicated by levels of ROS/MDA/protein carbonyl/nitrite/GSH etc. Further, 21 days prolonged administration of GS (10 mg/kg b.wt; once daily) protected against elastase-induced emphysema by mitigating expression/activity of MMP-2/-9 and increasing TIMP-1 expression. CONCLUSION: Overall, guggulsterone seems to be the key bioactive constituent responsible for exerting beneficial effects of C. wightii against COPD.
Assuntos
Enfisema , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Masculino , Camundongos , Animais , Elastase Pancreática , Commiphora/química , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Enfisema Pulmonar/metabolismo , Enfisema/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Anti-Inflamatórios/efeitos adversosAssuntos
Cistite/diagnóstico , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Meios de Contraste , Cistite/tratamento farmacológico , Cistite/microbiologia , Diagnóstico Diferencial , Enfisema/diagnóstico , Enfisema/tratamento farmacológico , Enfisema/microbiologia , Escherichia coli/isolamento & purificação , Feminino , Febre , Hidratação , Humanos , Klebsiella pneumoniae/isolamento & purificação , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity in vitro and in vivo efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.
Assuntos
Metaloproteinase 12 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Enfisema/tratamento farmacológico , Enfisema/etiologia , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Metaloproteinase 12 da Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Elastase Pancreática/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Relação Estrutura-AtividadeRESUMO
Hyaluronic acid (HA) is a key component of the extracellular matrix of the lungs. A unique attribute of HA is its water-retaining properties, so HA has a major role in the regulation of fluid balance in the lung interstitium. Hyaluronic acid has been widely used in the treatment of eyes, ears, joints and skin disorders, but in the last years, it has been also proposed in the treatment of certain lung diseases, including airway diseases, due to its anti-inflammatory and water-binding capacities. Hyaluronic acid aerosol decreases the severity of elastase-induced emphysema in murine models, prevents bronchoconstriction in asthmatics and improves some functional parameters in chronic obstructive pulmonary disease (COPD) patients. Due to the protection of HA against bronchoconstriction and its hydration properties, inhaled HA would increase the volume of airway surface liquid, resulting in mucus hydration, increased mucous transport and less mucous plugging of the airways. In addition, it has been seen in human studies that the treatment with nebulised HA improves the tolerability of nebulised hypertonic saline (even at 6% or 7% of concentration), which has been demonstrated to be an effective treatment in bronchial secretion management in patients with cystic fibrosis and bronchiectasis. Our objective is to review the role of HA treatment in the management of chronic airway diseases.
Assuntos
Asma/tratamento farmacológico , Bronquiectasia/tratamento farmacológico , Fibrose Cística/tratamento farmacológico , Enfisema/tratamento farmacológico , Ácido Hialurônico/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/fisiopatologia , Bronquiectasia/fisiopatologia , Fibrose Cística/fisiopatologia , Enfisema/fisiopatologia , Humanos , Ácido Hialurônico/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Elastase Pancreática/toxicidade , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death worldwide. Peroxynitrite, formed from nitric oxide, which is derived from inducible nitric oxide synthase, and superoxide, has been implicated in the development of emphysema, but the source of the superoxide was hitherto not characterized. Here, we identify the non-phagocytic NADPH oxidase organizer 1 (NOXO1) as the superoxide source and an essential driver of smoke-induced emphysema and pulmonary hypertension development in mice. NOXO1 is consistently upregulated in two models of lung emphysema, Cybb (also known as NADPH oxidase 2, Nox2)-knockout mice and wild-type mice with tobacco-smoke-induced emphysema, and in human COPD. Noxo1-knockout mice are protected against tobacco-smoke-induced pulmonary hypertension and emphysema. Quantification of superoxide, nitrotyrosine and multiple NOXO1-dependent signalling pathways confirm that peroxynitrite formation from nitric oxide and superoxide is a driver of lung emphysema. Our results suggest that NOXO1 may have potential as a therapeutic target in emphysema.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Enfisema/tratamento farmacológico , Enfisema/genética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/efeitos dos fármacos , Enfisema/etiologia , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Doença Pulmonar Obstrutiva Crônica/complicações , Transdução de Sinais/genética , Superóxidos/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Tirosina/análogos & derivados , Tirosina/metabolismoAssuntos
Cistite/diagnóstico por imagem , Enfisema/diagnóstico por imagem , Infecções por Klebsiella/diagnóstico por imagem , Dor Abdominal/microbiologia , Idoso , Antibacterianos/uso terapêutico , Bacteriúria/diagnóstico , Bacteriúria/tratamento farmacológico , Cistite/tratamento farmacológico , Cistite/microbiologia , Drenagem , Enfisema/tratamento farmacológico , Enfisema/microbiologia , Feminino , Humanos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/isolamento & purificação , Radiografia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE AND DESIGN: Gallic acid (GA) a naturally occurring phenolic compound, known to possess antioxidant/anti-inflammatory activities. The aim of the present work was to investigate the beneficial effects of GA against COPD-linked lung inflammation/emphysema by utilizing elastase (ET) and cigarette smoke (CS)-induced mice model. MATERIALS: Male BALB/c mice were treated with ET (1U/mouse) or exposed to CS (9 cigarettes/day for 4 days). GA administration was started 7 days (daily) prior to ET/CS exposure. Broncho-alveolar lavage was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung homogenate was assessed for MPO activity/GSH/MDA/protein carbonyls. Further, Lung tissue was subjected to semi-quantitative RT-PCR, immunoblotting, and histological analysis. RESULTS: GA suppressed the ET-induced neutrophil infiltration, elevated MPO activity and production of pro-inflammatory cytokines (IL-6/TNF-α/IL-1ß) at 24 h. Reduced inflammation was accompanied with normalization of redox balance as reflected by ROS/GSH/MDA/protein carbonyl levels. Further, GA suppressed phosphorylation of p65NF-κB and IκBα along with down-regulation of IL-1ß/TNF-α/KC/MIP-2/GCSF genes. Furthermore, GA offered protection against ET-induced airspace enlargement and ameliorated MMP-2/MMP-9. Finally, GA suppressed the CS-induced influx of neutrophils and macrophages and blunted gene expression of TNF-α/MIP-2/KC. CONCLUSION: Overall, our data show that GA effectively modulates pulmonary inflammation and emphysema associated with COPD pathogenesis in mice.
Assuntos
Anti-Inflamatórios/uso terapêutico , Enfisema/tratamento farmacológico , Ácido Gálico/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Enfisema/genética , Enfisema/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Elastase Pancreática , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumaça/efeitos adversos , Inibidor Tecidual de Metaloproteinase-1/genética , NicotianaRESUMO
Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key cellular defense mechanism against oxidative stress. Recent studies have shown that astaxanthin protects against oxidative stress via Nrf2. In this study, we investigated the emphysema suppression effect of astaxanthin via Nrf2 in mice. Mice were divided into four groups: control, smoking, astaxanthin, and astaxanthin + smoking. The mice in the smoking and astaxanthin + smoking groups were exposed to cigarette smoke for 12 weeks, and the mice in the astaxanthin and astaxanthin + smoking groups were fed a diet containing astaxanthin. Significantly increased expression levels of Nrf2 and its target gene, heme oxygenase-1 (HO-1), were found in the lung homogenates of astaxanthin-fed mice. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was significantly decreased, and emphysema was significantly suppressed. In conclusion, astaxanthin protects against oxidative stress via Nrf2 and ameliorates cigarette smoke-induced emphysema. Therapy with astaxanthin directed toward activating the Nrf2 pathway has the potential to be a novel preventive and therapeutic strategy for COPD.
Assuntos
Enfisema/induzido quimicamente , Enfisema/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Enfisema/patologia , Feminino , Heme Oxigenase-1/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Fumar , Xantofilas/farmacologiaAssuntos
Cistite/diagnóstico por imagem , Enfisema/diagnóstico por imagem , Pielonefrite/diagnóstico por imagem , Choque Séptico/etiologia , Dor Abdominal/etiologia , Antibacterianos/uso terapêutico , Cistite/complicações , Cistite/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Enfisema/tratamento farmacológico , Enfisema/etiologia , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Náusea/etiologia , Pielonefrite/complicações , Pielonefrite/tratamento farmacológico , Radiologia Intervencionista , Choque Séptico/tratamento farmacológico , Vômito/etiologiaRESUMO
AIMS: A rat model of emphysema was established that mimics the features of the human emphysema subtype and explores the effects of demethylation on lung function and blood tests. MATERIALS AND METHODS: Rats were randomly assigned to NO2, NO2â¯+â¯5-Azacytidine, and normal air groups based on a emphysema rat model induced by chronic NO2 exposure. This study estimates the characteristics of emphysema by conducting an analysis for IL-6 and TNF-α levels in bronchoalveolar lavage fluids (BALF) and plasma. Furthermore, CD68 macrophage immunofluorescent staining and inflammatory cell counts in BALF were compared between rats exposed to NO2 and normal air. KEY FINDINGS: 5-Azacytidine treatment led to restored ∆weight at 14 and 75â¯days of intervention and NO2â¯+â¯5-Azacytidine significantly reversed the effect of NO2 exposure on ∆weight. Intervention with 5-Azacytidine alleviated the decline of pulmonary function with a significant increase in FEV100/FVC% at 75â¯days in NO2â¯+â¯5-Azacytidine rats compared to NO2 rats. 5-Azacytidine reduced the counts of white blood cells (WBCs), granulocytes, lymphocytes, and monocytes at 14â¯days, but increased WBC, granulocyte, and monocyte counts at 45â¯days. Red blood cell counts, hemoglobin, and hematocrit concentrations were significantly reduced in NO2â¯+â¯5-Azacytidine rats. SIGNIFICANCE: This non-inflammatory rat emphysema model (induced by chronic NO2 exposure with global DNA hypomethylation and demethylation therapy with 5-Azacytidine) effectively improved emphysema by alleviating the decline of lung function and hypoxia, and slightly reinforced immune function. These results indicate the therapeutic potential of demethylation agents for the prevention and treatment of emphysema induced by the air pollutant NO2.
Assuntos
Azacitidina/metabolismo , Azacitidina/farmacologia , Enfisema/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Citocinas , Desmetilação/efeitos dos fármacos , Modelos Animais de Doenças , Enfisema/metabolismo , Enfisema/fisiopatologia , Interleucina-6/análise , Contagem de Leucócitos , Pulmão , Macrófagos , Masculino , Neutrófilos , Óxido Nítrico , Enfisema Pulmonar , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória/métodos , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND: Eucalyptol is a monoterpenoid oil present in many plants, principally the Eucalyptus species, and has been reported to have anti-inflammatory and antioxidative effects. HYPOTHESIS/PURPOSE: Since the potential effect of eucalyptol on mouse lung repair has not yet been studied, and considering that chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, the aim of this study was to investigate eucalyptol treatment in emphysematous mice. STUDY DESIGN: Male mice (C57BL/6) were divided into the following groups: control (sham-exposed), cigarette smoke (CS) (mice exposed to 12 cigarettes a day for 60 days), CSâ¯+â¯1â¯mg/ml (CS mice treated with 1â¯mg/ml eucalyptol for 60 days), and CSâ¯+â¯10â¯mg/ml (CS mice treated with 10â¯mg/ml eucalyptol for 60 days). Mice in the CS and control groups received vehicle for 60 days. Eucalyptol (or the vehicle) was administered via inhalation (15â¯min/daily). Mice were sacrificed 24â¯h after the completion of the 120-day experimental procedure. METHODS: Histology and additional lung morphometric analyses, including analysis of mean linear intercept (Lm) and volume density of alveolar septa (Vv[alveolar septa]) were performed. Biochemical analyses were also performed using colorimetric assays for myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) activity, in addition to using ELISA kits for the determination of inflammatory marker levels (tumor necrosis factor alpha [TNF-α], interleukin-1 beta [IL-1ß], interleukin 6 [IL-6], keratinocyte chemoattractant [KC], and tumor growth factor beta 1 [TGF-ß1]). Finally, we investigated protein levels by western blotting (nuclear factor (erythroid-derived 2)-like 2 [Nrf2], nuclear factor kappa B [NF-κB], matrix metalloproteinase 12 [MMP-12], tissue inhibitor of matrix metalloproteinase 1 [TIMP-1], neutrophil elastase [NE], and elastin). RESULTS: Eucalyptol promoted lung repair at the higher dose (10â¯mg/ml), with de novo formation of alveoli, when compared to the CS group. This result was confirmed with Lm and Vv[alveolar septa] morphometric analyses. Moreover, collagen deposit around the peribronchiolar area was reduced with eucalyptol treatment when compared to the CS group. Eucalyptol also reduced all inflammatory (MPO, TNF-α, IL-1ß, IL-6, KC, and TGF-ß1) and redox marker levels (MDA) when compared to the CS group (at least pâ¯<â¯0.05). In general, 10â¯mg/ml eucalyptol was more effective than 1â¯mg/ml and, at both doses, we observed an upregulation of SOD activity when compared to the CS group (pâ¯<â¯0.001). Eucalyptol upregulated elastin and TIMP-1 levels, and reduced neutrophil elastase (NE) levels, when compared to the CS group. CONCLUSION: In summary, eucalyptol promoted lung repair in emphysematous mice and represents a potential therapeutic phytomedicine in the treatment of COPD.
Assuntos
Enfisema/tratamento farmacológico , Eucaliptol/farmacologia , Fumar/efeitos adversos , Animais , Colágeno/metabolismo , Citocinas/metabolismo , Enfisema/induzido quimicamente , Enfisema/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Superóxido Dismutase/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
In this study, we aimed to investigate precise mechanism(s) of sphingolipid-imbalance and resulting ceramide-accumulation in COPD-emphysema. Where, human and murine emphysema lung tissues or human bronchial epithelial cells (Beas2b) were used for experimental analysis. We found that lungs of smokers and COPD-subjects with increasing emphysema severity demonstrate sphingolipid-imbalance, resulting in significant ceramide-accumulation and increased ceramide/sphingosine ratio, as compared to non-emphysema/non-smoker controls. Next, we found a substantial increase in emphysema chronicity-related ceramide-accumulation in murine (C57BL/6) lungs, while sphingosine levels only slightly increased. In accordance, the expression of the acid ceramidase decreased after CS-exposure. Moreover, CS-induced (sub-chronic) ceramide-accumulation was significantly (pâ¯<â¯0.05) reduced by treatment with TFEB/autophagy-inducing drug, gemfibrozil (GEM), suggesting that autophagy regulates CS-induced ceramide-accumulation. Next, we validated experimentally that autophagy/lipophagy-induction using an anti-oxidant, cysteamine, significantly (pâ¯<â¯0.05) reduces CS-extract (CSE)-mediated intracellular-ceramide-accumulation in p62â¯+â¯aggresome-bodies. In addition to intracellular-accumulation, we found that CSE also induces membrane-ceramide-accumulation by ROS-dependent acid-sphingomyelinase (ASM) activation and plasma-membrane translocation, which was significantly controlled (pâ¯<â¯0.05) by cysteamine (an anti-oxidant) and amitriptyline (AMT, an inhibitor of ASM). Cysteamine-mediated and CSE-induced membrane-ceramide regulation was nullified by CFTR-inhibitor-172, demonstrating that CFTR controls redox impaired-autophagy dependent membrane-ceramide accumulation. In summary, our data shows that CS-mediated autophagy/lipophagy-dysfunction results in intracellular-ceramide-accumulation, while acquired CFTR-dysfunction-induced ASM causes membrane ceramide-accumulation. Thus, CS-exposure alters the sphingolipid-rheostat leading to the increased membrane- and intracellular- ceramide-accumulation inducing COPD-emphysema pathogenesis that is alleviated by treatment with cysteamine, a potent anti-oxidant with CFTR/autophagy-augmenting properties.
Assuntos
Autofagia/efeitos dos fármacos , Ceramidas/metabolismo , Misturas Complexas/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Enfisema/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/efeitos adversos , Ceramidase Ácida/genética , Ceramidase Ácida/metabolismo , Animais , Antioxidantes/farmacologia , Autofagia/genética , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Estudos de Casos e Controles , Linhagem Celular , Misturas Complexas/isolamento & purificação , Cisteamina/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Enfisema/tratamento farmacológico , Enfisema/metabolismo , Enfisema/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Genfibrozila/farmacologia , Expressão Gênica , Humanos , Hipolipemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Nicotiana/efeitos adversos , Nicotiana/químicaRESUMO
Emphysematous pyelonephritis is a necrotic infection of the kidney characterized by the presence of gas within the renal parenchyma, the secretory cavities or the perirenal spaces. It is a severe condition that could be life-threatening. Patient's management remains controversial and is based either on surgery or on medical treatment. Percutaneous drainage can be also used for the treatment of these patients. We report 3 cases with EPN treated with only antibiotics. Patients' evolution was favorable. These results show that medical treatment could be sufficient.
Assuntos
Antibacterianos/uso terapêutico , Enfisema/tratamento farmacológico , Pielonefrite/tratamento farmacológico , Idoso , Enfisema/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Pielonefrite/fisiopatologia , Resultado do TratamentoRESUMO
Smoking cessation is the most effective treatment in patients with emphysema and lung inflammation. The aim of the present study was to examine the effect of varenicline, a smoking cessation drug, on emphysema in porcine pancreatic elastase (PPE)-inhaled mice. PPE-inhaled mice were treated with varenicline and an α7 nicotinic acetylcholine receptor (nAChR) antagonist, methyllycaconitine (MLA) for 5 and 21 days. Varenicline markedly ameliorated alveolar expansion and inflammatory response in bronchoalveolar lavage fluid in PPE-inhaled mice. These blocking effects were inhibited by MLA. Our findings demonstrate that varenicline likely has an anti-inflammatory property including reduced inflammatory cell recruitment in lung tissue to protect PPE-induced alveolar expansion via α7 nAChR.
Assuntos
Enfisema/induzido quimicamente , Enfisema/tratamento farmacológico , Agonistas Nicotínicos , Elastase Pancreática/efeitos adversos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Abandono do Hábito de Fumar , Vareniclina/farmacologia , Vareniclina/uso terapêutico , Aconitina/análogos & derivados , Aconitina/farmacologia , Aconitina/uso terapêutico , Administração por Inalação , Animais , Anti-Inflamatórios , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Enfisema/patologia , Camundongos Endogâmicos C57BL , Elastase Pancreática/administração & dosagem , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidoresRESUMO
Airway inflammation has been implicated in evoking progressive pulmonary disorders including chronic obstructive pulmonary disease (COPD) and asthma as a result of exposure to inhaled irritants, characterized by airway fibrosis, mucus hypersecretion, and loss of alveolar integrity. The current study examined whether oleuropein, a phenylethanoid found in olive leaves, inhibited pulmonary inflammation in experimental models of interleukin (IL)-4-exposed bronchial BEAS-2B epithelial cells and ovalbumin (OVA)- or cigarette smoke (CS)-exposed BALB/c mice. Nontoxic oleuropein at 1-20 µM diminished eotaxin-1-mediated induction of α-smooth muscle actin and mucin 5AC in epithelial cells stimulated by IL-4 at the transcriptional levels. Oral supplementation of 10-20 mg/kg oleuropein reduced the airway influx of eosinophils and lymphocytes as well as IL-4 secretion in lung promoted by OVA inhalation or CS. In addition, oleuropein suppressed infiltration of macrophages and neutrophils through blocking OVA inhalation- and CS-promoted induction of ICAM-1, F4/80, CD68, and CD11b in airways. OVA-exposed pulmonary fibrosis was detected, while alveolar emphysema was evident in CS-exposed mouse lungs. In alveolar epithelial A549 cells exposed to CS extracts, oleuropein attenuated apoptotic cell loss. Collectively, oleuropein inhibited pulmonary inflammation leading to asthmatic fibrosis and alveolar emphysema driven by influx of inflammatory cells in airways exposed OVA or CS. Therefore, oleuropein may be a promising anti-inflammatory agent for treating asthma and COPD.