Alfonso Torrego

Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma

Background: About 5–10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1). Methods: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 μg/ml) and dexamethasone (10−8 and 10−6 M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. Results: The inhibition of LPS-induced interleukin (IL)1β, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α release by dexamethasone (10−6 M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma. Conclusion: Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.

Inflammatory biomarkers in airways of patients with severe asthma compared with non‐severe asthma

Background About 5–10% of patients with asthma suffer from poorly‐controlled disease despite corticosteroid (CS) therapy.

Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis

Background: The angiotensin system has a role in the pathogenesis of pulmonary fibrosis. This study examines the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in bleomycin induced lung fibrosis and its possible implication in the regulation of prostaglandin E2 (PGE2) synthesis and cyclooxygenase-2 (COX-2) expression. Methods: Rats were given a single intratracheal instillation of bleomycin (2.5 U/kg). Losartan (50 mg/kg/day) was administrated orally starting one day before induction of lung fibrosis and continuing to the conclusion of each experiment. Results: Losartan reduced the inflammation induced by bleomycin, as indicated by lower myeloperoxidase activity and protein content in the bronchoalveolar lavage fluid. Collagen deposition induced by bleomycin was inhibited by losartan, as shown by a reduction in the hydroxyproline content and the amelioration of morphological changes. PGE2 levels were lower in fibrotic lungs than in normal lungs. Losartan significantly increased PGE2 levels at both 3 and 15 days. A reduction in COX-2 expression by bleomycin was seen at 3 days which was relieved by losartan. Conclusions: The antifibrotic effect of losartan appears to be mediated by its ability to stimulate the production of PGE2. Losartan, which is already widely used clinically, could be assessed as a new treatment in lung fibrosis.

Molecular mechanisms of glucocorticoids

Inflammatory processes are central to many respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and many types of diffuse interstitial lung disease. The specific characteristics of the inflammatory response and inflammation site vary according to the disease, but recruitment and activation of different inflammatory cells and changes in structural cells of the lung are implicated in all of them. Glucocorticoids are currently the most potent antiinflammatory drugs available. In fact, glucocorticoids, whether administered systemically or by inhalation, are the first-line drugs in the treatment of many of these inflammatory processes.1 Many pharmacological applications have been found since the first molecule with glucocorticoid activity was identified in 1937,2 and the chemical properties of these molecules have been constantly improved. Their antiinflammatory properties in the treatment of rheumatoid arthritis were first discovered in the 1950s. We have only recently, however, made progress in understanding the mechanism of action of these drugs thanks to the development of new molecular biology techniques. The aforementioned diseases are characterized by increased expression of a variety of proteins such as cytokines, chemokines, inflammatory enzymes, receptors, and adhesion molecules implicated in complex inflammatory cascades. Upregulation of these inflammatory proteins is caused by greater transcription of inflammatory genes which are not normally expressed by the affected cells. The expression of these inflammatory genes during inflammatory processes is specific to each cell.3 A better understanding of the mechanism of action of these drugs would help rationalize their use and favor the development of new compounds with specific effects. Glucocorticoids: Structure and Function

Mecanismos moleculares de los glucocorticoides

La inflamación es el hallazgo central de muchas afecciones respiratorias, como el asma, la enfermedad pulmonar obstructiva crónica (EPOC), la fibrosis quística o muchas enfermedades pulmonares intersticiales difusas. Las características específicas de la respuesta inflamatoria y sitio de inflamación difieren entre estas enfermedades, pero todas presentan reclutamiento y activación de diferentes células inflamatorias y cambios en las células estructurales del pulmón. Los glucocorticoides (GC) son, en el momento actual, los fármacos disponibles con mayor actividad antiinflamatoria. De hecho los GC son, bien por vía sistémica, bien por vía inhalada, el fármaco de primera línea en el tratamiento de muchos de estos procesos inflamatorios. Desde la identificación de la primera molécula con actividad glucocorticoidea en 1937 hasta nuestros días, han sido numerosas las aplicaciones farmacológicas y las mejoras químicas de estos compuestos. Desde los años cincuenta se conocen sus propiedades antiinflamatorias, inicialmente observadas en la artritis reumatoide. Sin embargo, no ha sido hasta recientemente que hemos avanzado en el conocimiento del mecanismo molecular de acción de estos fármacos gracias al desarrollo de nuevas técnicas de biología molecular. Las enfermedades mencionadas se caracterizan por una expresión aumentada de múltiples proteínas que están implicadas en complejas cascadas inflamatorias. Estas proteínas incluyen citocinas, quimiocinas, enzimas que producen mediadores inflamatorios, receptores de mediadores inflamatorios y moléculas de adhesión. El aumento de la expresión de estas proteínas inflamatorias es el resultado de una mayor transcripción de genes inflamatorios, genes que las células afectadas no expresan normalmente, pero que se expresan en los procesos inflamatorios de una forma específica para cada célula. Un mejor conocimiento del mecanismo de acción de estos fármacos ayuda a hacer un uso más racional de ellos y a favorecer el desarrollo de nuevos compuestos con efectos específicos.

Capsaicin cough sensitivity in bronchiectasis

Background: Bronchiectasis is a suppurative airway disease characterised by persistent cough and sputum production associated with bronchial dilatation. A study was undertaken to determine whether cough sensitivity is increased in bronchiectatic patients. Methods: Twenty two patients with bronchiectasis and 20 healthy non-smoking controls matched for age and sex were recruited into the study. Quality of life (Leicester Cough Questionnaire score), total cough symptom score, and extent of bronchiectasis on HRCT scans were recorded. Cough sensitivity was assessed using incremental inhalation of capsaicin concentrations; the concentration at which 5 or more coughs occurred (C5) was recorded. Results: Patients with bronchiectasis had increased sensitivity to capsaicin compared with controls (mean (SE) log10 C5 1.22 (0.20) v 1.89 (0.21); p<0.03). Capsaicin sensitivity correlated positively with the Leicester Cough Questionnaire score (r = 0.64; p = 0.005) and inversely with the total cough symptom score (r = −0.58; p = 0.004), but not with the extent of the disease. It also correlated with forced expiratory volume in 1 second (FEV1) in litres (r = 0.58; p = 0.005) but not with FEV1 % predicted. Capsaicin sensitivity was not related to the presence of infected sputum or to corticosteroid or bronchodilator use. Conclusions:: Patients with bronchiectasis have a sensitive cough reflex which reflects the severity of cough symptoms. A measure of cough severity could be part of health assessment for patients with bronchiectasis.

Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD

BACKGROUND Combination inhaled therapy with long-acting β2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain. METHODS Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay. RESULTS Nuclear GR significantly increased after the inhalation of FP 500 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1β-induced CXCL8 (P < .05). CONCLUSIONS Addition of SLM 50 μg to FP 100 μg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.

No effect of omeprazole on pH of exhaled breath condensate in cough associated with gastro-oesophageal reflux

BackgroundEndogenous airway acidification evaluated as pH in exhaled breath condensate (EBC) has been described in patients with chronic cough. Proton pump inhibitors improve gastro-oesophageal reflux (GOR)-associated cough.MethodsWe examined pH levels in EBC and capsaicin cough response in 13 patients with chronic cough (mean age 41 years, SD 9) associated with GOR before and after omeprazole treatment (40 mg/day for 14 days) and its relationship with clinical response.ResultsOmeprazole abolished symptoms associated with GOR. Patients with chronic cough had an EBC pH of 8.28 (SD 0.13) prior to treatment but this did not change with omeprazole treatment. There was a significant improvement in the Leicester Cough Questionnaire symptom scores from 80.8 points (SD 13.2) to 95.1 (SD 17) (p = 0.02) and in a 6-point scale of cough scores, but there was no change in capsaicin cough response.ConclusionAn improvement in GOR-associated cough was not associated with changes in EBC pH or capsaicin cough response. These parameters are not useful markers of therapeutic response.

Neumonitis por hipersensibilidad tras exposición a Candida spp

Hypersensitivity pneumonitis (HP) is a lung disease caused by heavy and recurrent inhalation of antigens. We describe the case of a patient with HP caused by domestic exposure to Candida spp. The diagnosis was made by taking into consideration the, clinical presentation, exposure history, radiological findings, bronchoalveolar lavage, lung function and the immuno-allergy study. The diagnosis was definitively confirmed by performing a specific bronchial provocation test. It has been shown that there is cross-reactivity between different Candida species, and despite making the diagnosis in this case with Candida albicans, we were unable to define exactly which species was responsible for the HP.

Hypersensitivity pneumonitis after exposure to Candida spp

Abstract Hypersensitivity pneumonitis (HP) is a lung disease caused by heavy and recurrent inhalation of antigens. We describe the case of a patient with HP caused by domestic exposure to Candida spp. The diagnosis was made by taking into consideration the clinical presentation, exposure history, radiological findings, bronchoalveolar lavage, lung function and the immuno-allergy study. The diagnosis was definitively confirmed by performing a specific bronchial provocation test. It has been shown that there is crossreactivity between different Candida species, and despite making the diagnosis in this case with Candida albicans, we were unable to define exactly which species was responsible for the HP.