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1.
Allergy ; 79(5): 1089-1122, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38108546

RESUMEN

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.


Asunto(s)
Senescencia Celular , Redes y Vías Metabólicas , Humanos , Senescencia Celular/efectos de los fármacos , Animales , Enfermedad Crónica , Inflamación/metabolismo , Inflamación/inmunología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/inmunología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Envejecimiento/inmunología , Envejecimiento/metabolismo
2.
medRxiv ; 2020 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-32909007

RESUMEN

The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.

3.
Int J Cardiol ; 309: 40-47, 2020 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-32223963

RESUMEN

BACKGROUND: Heart surgery with cardio-pulmonary bypass (CPB) is associated with lung ischemia leading to injury and inflammation. It has been suggested this is a result of the lungs being kept deflated throughout the duration of CPB. Low frequency ventilation (LFV) during CPB has been proposed to reduce lung dysfunction. METHODS: We used a semi-biased multi-omic approach to analyse lung biopsies taken before and after CPB from 37 patients undergoing coronary artery bypass surgery randomised to both lungs left collapsed or using LFV for the duration of CPB. We also examined inflammatory and oxidative stress markers from blood samples from the same patients. RESULTS: 30 genes were induced when the lungs were left collapsed and 80 by LFV. Post-surgery 26 genes were significantly higher in the LFV vs. lungs left collapsed, including genes associated with inflammation (e.g. IL6 and IL8) and hypoxia/ischemia (e.g. HIF1A, IER3 and FOS). Relatively few changes in protein levels were detected, perhaps reflecting the early time point or the importance of post-translational modifications. However, pathway analysis of proteomic data indicated that LFV was associated with increased "cellular component morphogenesis" and a decrease in "blood circulation". Lipidomic analysis did not identify any lipids significantly altered by either intervention. DISCUSSION: Taken together these data indicate the keeping both lungs collapsed during CPB significantly induces lung damage, oxidative stress and inflammation. LFV during CPB increases these deleterious effects, potentially through prolonged surgery time, further decreasing blood flow to the lungs and enhancing hypoxia/ischemia.


Asunto(s)
Puente Cardiopulmonar , Proteómica , Puente Cardiopulmonar/efectos adversos , Puente de Arteria Coronaria/efectos adversos , Humanos , Pulmón/cirugía , Respiración
4.
BMC Cancer ; 18(1): 1238, 2018 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-30526542

RESUMEN

BACKGROUND: COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC). METHODS: Using a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a ≥ 2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue. RESULTS: The expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p < 0.05). CONCLUSION: PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and patient mortality may be mediated through the induction of specific macrophage phenotypes.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/etiología , Neoplasias Pulmonares/etiología , Macrófagos Alveolares/metabolismo , Proteínas Mitocondriales/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Transcriptoma
5.
Allergy ; 72(5): 737-753, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27696462

RESUMEN

BACKGROUND: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics. AIM: We developed and characterized a robust, consistent, and reproducible mouse model of severe exacerbation of chronic allergic asthma. METHODS: Chronic allergic airway inflammation was induced following a house dust mite (HDM) sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled fluticasone propionate (FP), systemic corticosteroids (Pred), or anti-IL-5. Mice were killed at different time points after infection: Cellular accumulation and cytokines levels in the airways, PenH as a measure of airway hyper-responsiveness (AHR), and lung histology and viral replication were assessed. RESULTS: Infection with low-dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial, and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14 h after virus exposure by a marked innate, but no Th2 and Th1 response subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic, and T cells into the lung lumen, parenchyma, and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation. CONCLUSIONS: Together, these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote the development of novel therapeutics.


Asunto(s)
Asma/etiología , Asma/patología , Tolerancia a Medicamentos , Inmunidad Innata , Virus de la Influenza A , Interleucina-5/antagonistas & inhibidores , Infecciones por Orthomyxoviridae/complicaciones , Esteroides/farmacología , Alérgenos/inmunología , Anfirregulina/biosíntesis , Animales , Antiasmáticos/farmacología , Anticuerpos Monoclonales/farmacología , Asma/tratamiento farmacológico , Biopsia , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Eosinófilos/inmunología , Eosinófilos/metabolismo , Fluticasona/farmacología , Inmunización , Masculino , Ratones , Infecciones por Orthomyxoviridae/virología , Pyroglyphidae/inmunología , Carga Viral
6.
Mucosal Immunol ; 9(4): 859-72, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26555706

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.


Asunto(s)
Inflamación/inmunología , Pulmón/inmunología , Monocitos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , ARN Mensajero/genética , Mucosa Respiratoria/fisiología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Animales , Apoptosis , Modelos Animales de Enfermedad , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Fumar/efectos adversos , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Regulación hacia Arriba
7.
Lung Cancer ; 90(2): 121-7, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26363803

RESUMEN

Both COPD and lung cancer are major worldwide health concerns owing to cigarette smoking, and represent a huge, worldwide, preventable disease burden. Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking. Lung cancer and COPD may be different aspects of the same disease, with the same underlying predispositions, whether this is an underlying genetic predisposition, telomere shortening, mitochondrial dysfunction or premature aging. In the majority of smokers, the burden of smoking may be dealt with by the body's defense mechanisms: anti-oxidants such as superoxide dismutases, anti-proteases and DNA repair mechanisms. However, in the case of both diseases these fail, leading to cancer if mutations occur or COPD if damage to the cell and proteins becomes too great. Alternatively COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage, chronic exposure to pro-inflammatory cytokines, repression of the DNA repair mechanisms and increased cellular proliferation. Understanding the mechanisms that drive these processes in primary cells from patients with these diseases along with better disease models is essential for the development of new treatments.


Asunto(s)
Neoplasias Pulmonares/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Fumar/genética , Animales , Daño del ADN/genética , Humanos , Estrés Oxidativo/genética
8.
Curr Pharm Des ; 17(7): 674-84, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21406059

RESUMEN

The disproportionate cost of treating asthmatic patients who do not respond to conventional anti-inflammatory therapies makes delineation of the mechanism for glucocorticoid resistance an important field of asthma research. Unbiased cluster analysis indicates that asthma is a syndrome with a number of distinct phenotypes and 5-10% of asthmatics fall into this category of relative glucocorticoid insensitivity. This sub-population is itself divided into smaller subsets which have different underlying mechanisms for this relative glucocorticoid resistance ranging from an inherited genetic basis to specific kinase signalling pathways triggered by exposure to environmental stressors such as cigarette smoking or infection. Whilst the underlying mechanisms are becoming better understood there remains a lack of effective novel therapies. However it is clear that relative glucocorticoid insensitive patients who are smokers should be encouraged to quit, thereby reducing their oxidant load. Novel treatments will consist of either developing new anti-inflammatory treatments targeting pathways aberrantly activated in these patients or of suppressing signalling pathways that attenuate glucocorticoid receptor function and thereby restoring glucocorticoid sensitivity. It will be important to uncover non-invasive biomarkers for aberrant pathway activation and for discerning which components of glucocorticoid receptor activation are abnormal if future treatments are to be tailored to address these specific issues. Conventional combination therapies will continue to be used in the near future but additional add-on treatments using drugs directed against aberrantly expressed inflammatory pathways or mediators along with an inhaled glucocorticoid are likely to prove the most effective new therapies in the future.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Esteroides/uso terapéutico , Animales , Antiasmáticos/farmacología , Asma/inmunología , Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/inmunología , Predicción , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Humanos , Receptores de Glucocorticoides/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Esteroides/farmacología
9.
Eur Respir J ; 37(4): 813-22, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20693255

RESUMEN

Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points. Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg⁻¹·day⁻¹, 1.25 mg·kg⁻¹ and 2.5 mg·kg⁻¹·48 h⁻¹) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro. Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.


Asunto(s)
Dexametasona/farmacología , Pulmón/efectos de los fármacos , Monocrotalina/farmacología , Músculo Liso/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Proliferación Celular , Hipertensión Pulmonar Primaria Familiar , Hemodinámica , Hipertensión Pulmonar/tratamiento farmacológico , Inmunohistoquímica/métodos , Interleucina-6/metabolismo , Masculino , Ratas , Ratas Wistar , Resultado del Tratamiento
10.
Eur Respir J ; 36(5): 1143-54, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19840968

RESUMEN

Chronic obstructive pulmonary disease (COPD) is a major health problem and cigarette smoke is the main risk factor for the development of COPD. The characteristic changes in airway morphology, inflammatory cell infiltration and mediator expression in COPD may result from direct effects of cigarette smoke on airway cells. Toll-like receptors (TLRs) are key elements in pathogen recognition by the host immune system. Although TLRs have been intensely studied in innate immunity and infection, their critical role in noninfectious challenges has only recently emerged. Here we investigate whether cigarette smoke induces TLR9 signalling in human neutrophils. Human neutrophils were isolated from buffy coat and exposed to cigarette smoke extract. The production of CXC chemokine ligand (CXCL)8 was measured as a functional readout and the role of TLR9 signalling was investigated. Cigarette smoke extract induced CXCL8 release via TLR9 activation in neutrophils, which was confirmed in TLR9 stably transfected human embryonic kidney 293 cells. Moreover, cigarette smoke extract upregulated the expression of TLR9 and the upregulated expression was suppressed by N-acetylcysteine. TLR9 mediates cigarette smoke-induced release of CXCL8 and this may contribute to the accumulation of neutrophils and inflammation within the airways of smokers.


Asunto(s)
Interleucina-8/metabolismo , Neutrófilos/metabolismo , Neumonía/inmunología , Fumar/inmunología , Receptor Toll-Like 9/metabolismo , Células HEK293 , Humanos , Interleucina-8/genética , Interleucina-8/inmunología , FN-kappa B/genética , FN-kappa B/metabolismo , Neutrófilos/citología , Óxido Nítrico/metabolismo , Neumonía/epidemiología , Neumonía/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Transducción de Señal/inmunología , Fumar/epidemiología , Fumar/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología , Transfección
11.
Thorax ; 64(11): 968-75, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19703829

RESUMEN

BACKGROUND: Increased numbers of activated neutrophils have been reported in the bronchial mucosa of patients with stable chronic obstructive pulmonary disease (COPD), particularly in severe disease. OBJECTIVES: To investigate the expression of neutrophilic chemokines and adhesion molecules in bronchial biopsies from patients with stable COPD of different severity (GOLD stages I-IV) compared with age-matched control subjects, smokers with normal lung function and never smokers. METHODS: The expression of CCL5, CXCL1, 5, 6, 7 and 8, CXCR1, CXCR2, CD11b and CD44 was measured in the bronchial mucosa using immunohistochemistry, confocal immunofluorescence, real-time quantitative polymerase chain reaction (RT-QPCR) and Western blotting (WB). RESULTS: The numbers of CCL5+ epithelial cells and CCL5+ and CXCL7+ immunostained cells were increased in the bronchial submucosa of patients with stable severe COPD compared with control never smokers and smokers with normal lung function. This was also confirmed at the level of mRNA expression. The numbers of CCL5+ cells in the submucosa of patients with COPD were 2-15 times higher than any other chemokines. There was no correlation between the number of these cells and the number of neutrophils in the bronchial submucosa. Compared with control smokers, the percentage of neutrophils co-expressing CD11b and CD44 receptors was significantly increased in the submucosa of patients with COPD. CONCLUSION: The increased expression of CCL5 and CXCL7 in the bronchial mucosa of patients with stable COPD, together with an increased expression of extracellular matrix-binding receptors on neutrophils, may be involved in the pathogenesis of COPD.


Asunto(s)
Quimiocina CCL5/metabolismo , Quimiocinas CXC/metabolismo , Activación Neutrófila , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Aguda , Anciano , Bronquios/inmunología , Bronquios/metabolismo , Antígenos CD11/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Elastasa de Leucocito/metabolismo , Masculino , Persona de Mediana Edad , Activación Neutrófila/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Pruebas de Función Respiratoria , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo
12.
Clin Pharmacol Ther ; 86(1): 49-53, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19357642

RESUMEN

Smokers with asthma show a reduced response to inhaled corticosteroids. We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist would be superior for the clinical treatment of these asthma patients. Forty-six smokers with asthma were randomized to inhaled beclometasone dipropionate (200 microg per day) or rosiglitazone (8 mg per day) for 4 weeks. Rosiglitazone produced improvements in lung function (forced expiratory volume in 1 s (FEV(1)) = 183 ml, P = 0.051; forced expiratory flow between 25 and 75% of the forced vital capacity (FEF(25-75)) = 0.24 l/s, P = 0.030) as compared with inhaled beclometasone dipropionate. Further trials using PPAR-gamma agonists in steroid-resistant airway disease are indicated.


Asunto(s)
Asma/tratamiento farmacológico , Broncodilatadores/administración & dosificación , PPAR gamma/agonistas , Fumar/tratamiento farmacológico , Tiazolidinedionas/administración & dosificación , Adulto , Asma/complicaciones , Asma/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , PPAR gamma/fisiología , Rosiglitazona , Fumar/efectos adversos , Fumar/fisiopatología
13.
Eur Respir J ; 33(5): 1010-7, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19196814

RESUMEN

Smoking is common in asthma and is associated with worse asthma control and a reduced therapeutic response to corticosteroids. The present authors hypothesised that treating smokers with asthma with low-dose theophylline added to inhaled corticosteroids would enhance steroid sensitivity and thereby improve lung function and symptoms. In a double-blind, parallel group exploratory trial, 68 asthmatic smokers were randomised to one of three treatments for 4 weeks: inhaled beclometasone (200 microg day(-1)), theophylline (400 mg day(-1)) or both treatments combined. Outcome measures included change in lung function and Asthma Control Questionnaire (ACQ) scores. At 4 weeks, theophylline added to inhaled beclometasone produced an improvement in peak expiratory flow (39.9 L min(-1), 95% confidence intervals (CI) 10.9-68.8) and ACQ score (-0.47, 95% CI -0.91- -0.04) and a borderline improvement in pre-bronchodilator forced expiratory volume in one second (mean difference 165 mL, 95% CI -13-342) relative to inhaled corticosteroid alone. Theophylline alone improved the ACQ score (-0.55, 95% CI -0.99- -0.11), but not lung function. In the present pilot study, the combination of low-dose theophylline and inhaled beclometasone produced improvements in both lung function and symptoms in a group of smokers with asthma. Larger trials are required to extend and confirm these findings.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Beclometasona/uso terapéutico , Broncodilatadores/uso terapéutico , Fumar/fisiopatología , Teofilina/uso terapéutico , Administración por Inhalación , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Antiasmáticos/administración & dosificación , Broncodilatadores/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Pruebas de Función Respiratoria , Estadísticas no Paramétricas , Resultado del Tratamiento
14.
Eur Respir J ; 31(6): 1334-56, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18515558

RESUMEN

Chronic obstructive pulmonary disease is a leading global cause of morbidity and mortality that is characterised by inexorable deterioration of small airways obstruction with emphysema associated with cellular inflammation and structural remodelling. Other features include apoptosis as well as proliferation of cells, and both tissue repair and lack of tissue repair. Metalloprotease release, together with that of apoptotic factors, may underlie the emphysema, and, conversely, fibrosis of the small airways may be accounted for by the effects of growth factor activation. In advanced disease, influential factors include the development of autoimmunity, with activation of dendritic cells and T-helper cells of both type 1 and 2, and the senescence response. An inability of macrophages to ingest apoptosed cells and bacteria may exacerbate inflammatory responses. Systemic inflammation with concomitant cardiovascular disease and metabolic syndrome may reflect the effect of cigarette smoke on nonpulmonary cells. Corticosteroid resistance may be secondary to oxidative stress mechanisms, such as inactivation of histone deacetylases. The mechanisms of chronic obstructive pulmonary disease may be heterogeneous, according to severity, and clinical phenotypes need to be correlated with cellular and pathological processes. Treatments may be targeted to patients with specific mechanisms.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Fumar/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/fisiopatología , Ratones , Estrés Oxidativo/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/patología , Ratas , Sistema Respiratorio/inmunología , Sistema Respiratorio/patología , Fumar/inmunología
15.
Clin Exp Allergy ; 38(5): 805-11, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18325031

RESUMEN

BACKGROUND: Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist possessing some anti-inflammatory effects although the molecular mechanism of these anti-inflammatory effects is unknown. In this study, we aimed to investigate the effect of montelukast on nuclear factor (NF)-kappaB-associated histone acetylation activity in phorbol myristate acetate (PMA)-differentiated U937 cells. METHODS: We examined the inhibitory effects of montelukast on TNF-alpha-induced IL-8 production in PMA-differentiated U-937 cells. U-937 cells were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages. Macrophages were then exposed to TNF-alpha (10 ng/mL) in the presence or absence of montelukast (0.01-10 microm) for 24 h. After this time, the concentration of IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The effect of signalling pathways on TNF-alpha-induced IL-8 release was examined pharmacologically using selective NF-kappaB/IKK2 (AS602868, 3 microm), (PD98059, 10 microm) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 microm) inhibitors. NF-kappaB DNA binding activity was measured by a DNA-binding ELISA-based assay. NF-kappaB-p65-associated histone acetyltransferase (HAT) activity was measured by immunoprecipitation linked to commercial fluorescent HAT. RESULTS: TNF-alpha-induced IL-8 release was suppressed by an NF-kappaB inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a concentration-dependent inhibition of TNF-alpha-induced IL-8 release and mRNA expression that reached a plateau at 0.1 microm without affecting cell viability. Montelukast did not affect NF-kappaB p65 activation as measured by DNA binding but suppressed NF-kappaB p65-associated HAT activity. CONCLUSION: Montelukast inhibits TNF-alpha-stimulated IL-8 expression through changes in NF-kappaB p65-associated HAT activity. Drugs targeting these enzymes may enhance the anti-inflammatory actions of montelukast.


Asunto(s)
Acetatos/farmacología , Histona Acetiltransferasas/antagonistas & inhibidores , Interleucina-8/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Macrófagos/efectos de los fármacos , Quinolinas/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Ciclopropanos , Humanos , Interleucina-8/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Sulfuros , Células U937
16.
Clin Exp Immunol ; 150(1): 151-7, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17711487

RESUMEN

There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the effect of two glucocorticoids (dexamethasone and triamcinolone acetonide) on reducing lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-alpha-induced interleukin (IL)-8 release in a monocytic cell line and two lymphocytic cell lines (HUT-78 and Jurkat). The effect of the histone deacetylase inhibitor trichostatin A (TSA) on LPS- and TNF-alpha-induced IL-8 release and its repression by glucocorticoids was also examined. LPS and TNF-alpha induced IL-8 release in all three cell lines and this induction was inhibited by both dexamethasone and triamcinolone. Pretreatment of cells with TSA enhanced basal and LPS- and TNFalpha-stimulated IL-8 release in all three cell lines. TSA also attenuated the inhibitory effect of glucocorticoids on stimulated IL-8 release. Chromatin immunoprecipitation assays confirmed that LPS and TNF-alpha enhanced histone acetylation at the IL-8 promoter and that this was inhibited by triamcinolone in all three cell types. Changes in histone acetylation at the IL-8 are important in its regulation by proinflammatory and anti-inflammatory agents, and modulation of this activity may have therapeutic potential in inflammatory conditions.


Asunto(s)
Glucocorticoides/farmacología , Interleucina-8/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Acetilación , Dexametasona/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Interleucina-8/genética , Lipopolisacáridos/inmunología , Linfocitos/inmunología , Macrófagos/inmunología , Triamcinolona Acetonida/farmacología , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/inmunología
17.
Br J Pharmacol ; 150(7): 829-31, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17325655

RESUMEN

Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by changes in the acetylation status of histones and non-histone proteins. Many human diseases, particularly cancer, have been associated with altered patterns of histone acetylation. Furthermore, abnormal expression and activation of histone acetyltransferases, which act as transcriptional co-activators, has been reported in inflammatory diseases. Histone deacetylase (HDAC) inhibitors have been developed clinically for malignancies due to their effects on apoptosis. More recently, in vitro and in vivo data indicates that HDAC inhibitors may be anti-inflammatory due to their effects on cell death acting through acetylation of non-histone proteins. Although there are concerns over the long-term safety of these agents, they may prove useful particularly in situations where current anti-inflammatory therapies are suboptimal.


Asunto(s)
Antiinflamatorios/uso terapéutico , Inhibidores de Histona Desacetilasas , Inflamación/tratamiento farmacológico , Animales , Humanos
18.
Eur Respir J ; 28(1): 219-42, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16816350

RESUMEN

Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (c-Jun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-kappaB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-kappaB-mediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of kappaB-alpha kinase or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-kappaB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression. Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity. The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/quercetin and reserveratol), specific spin traps, such as alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-kappaB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.


Asunto(s)
Oxidación-Reducción , Estrés Oxidativo , Neumonía/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Antioxidantes/farmacología , Glucocorticoides/metabolismo , Glutatión/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Inflamación , Lípidos/química , Modelos Biológicos , FN-kappa B/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Especies Reactivas de Oxígeno
19.
Monaldi Arch Chest Dis ; 63(2): 84-7, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16128222

RESUMEN

BACKGROUND: Little is known about the long-term natural history of asthma and the long-term clinical and functional consequences in non-smoking patients. From a functional point of view, non-smoking asthmatic patients may have a significantly greater decline in forced expiratory volume in one second (FEV1) compared with non-asthmatic subjects and may develop chronic irreversible (fixed) airflow limitation. This has been related to the physiological consequences of chronic airway inflammation causing airway remodeling. However these lesions are all potentially reversible and there is little radiological evidence indicating lung destruction (pulmonary emphysema), which is potentially irreversible, in non-smoking asthmatics. Severe chronic respiratory failure is the major cause of mortality in patients with severe chronic lung diseases. Domiciliary long-term oxygen therapy (LTOT) is an accepted treatment for patients with severe chronic respiratory failure. Our reasoning, therefore, was that if asthma is a cause of severe chronic respiratory failure in non-smokers we should be able to find non-smoking asthmatics within a large population of patients on LTOT. The aim of our study (Asthma and Long-term Oxygen Therapy, "ALOT") was to investigate the prevalence of non-smoking asthmatics in patients on LTOT in a multi-centre, cross-sectional study. METHODS: Between June and September 2003 we screened all subjects on long-term domiciliary oxygen therapy in three different hospitals in the North-East area of Italy (within the provinces of Ferrara and Bologna). Taken collectively, we have found one-hundred and eighty-four patients on LTOT. We have reviewed their clinical data (age, sex, smoking, history and physical examination, arterial blood gas analysis, pulmonary function). RESULTS: 114 patients (all smokers) fulfilled the diagnostic criteria for COPD. Seventy patients (all smokers) had other diseases. We were unable to find any non-smokers in our screened population of subjects on long-term domiciliary oxygen therapy. Furthermore, there was no past history of asthma and/or acute wheezing episodes in either of the patient groups. CONCLUSIONS: This data suggests that asthma is an uncommon cause of severe chronic respiratory failure necessitating long-term domiciliary oxygen therapy in non-smokers and supports the current consensus that asthma and COPD are different diseases with differing stages of severity and the concept that long-term avoidance of active smoking is fundamental for the prevention of severe chronic respiratory failure.


Asunto(s)
Asma/complicaciones , Insuficiencia Respiratoria/etiología , Anciano , Dióxido de Carbono/sangre , Enfermedad Crónica , Estudios Transversales , Femenino , Volumen Espiratorio Forzado/fisiología , Servicios de Atención de Salud a Domicilio , Humanos , Estudios Longitudinales , Masculino , Oxígeno/sangre , Terapia por Inhalación de Oxígeno , Examen Físico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Insuficiencia Respiratoria/terapia , Fumar/efectos adversos , Fumar/fisiopatología , Capacidad Pulmonar Total/fisiología , Capacidad Vital/fisiología
20.
Eur Respir J ; 25(3): 552-63, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15738302

RESUMEN

Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappa B. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse steroid resistance in chronic obstructive pulmonary disease and other inflammatory diseases.


Asunto(s)
Acetiltransferasas/metabolismo , Histonas/metabolismo , Inflamación/enzimología , Enfermedades Respiratorias/enzimología , Acetilación , Acetiltransferasas/química , Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Asma/enzimología , Broncodilatadores/uso terapéutico , Ensamble y Desensamble de Cromatina , Resistencia a Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Histonas/química , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/enzimología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Enfermedades Respiratorias/complicaciones , Enfermedades Respiratorias/tratamiento farmacológico , Teofilina/uso terapéutico
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