0000000000004052
AUTHOR
Julio Cortijo Gimeno
Role of MUC4 in idiopathic pulmonary fibrosis
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible form of fibrotic intersticial lung disease, characterized by uncontrolled fibroblast proliferative processes and alveolar type II epithelial dysfunction. MUC4, a multi-domain transmembrane glycoprotein, is often overexpressed in epithelial cancers, with consequences for the biological properties, involved in cellular processes related to IPF. However, the role of MUC4 in IPF has not beet studied yet. Objective: To analyze the implication of MUC4 in IPF Methods: Lung tissue from 14 healthy and 14 IPF patients was obtained. MUC4 expression was analyzed by western blot, RT-PCR and immunohistochemistry. T…
Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro
BACKGROUND AND PURPOSEMucociliary malfunction occurs in chronic obstructive pulmonary disease (COPD) and compromised functions of ciliated bronchial epithelial cells may contribute to this. Cigarette smoke, a major risk factor for COPD, impairs ciliary beat frequency (CBF). cAMP augments CBF. This in vitro study addressed, in differentiated, primary human bronchial epithelial cells, whether roflumilast N-oxide, a PDE4 inhibitor, (i) augments CBF; (ii) prevents the reduction in CBF induced by cigarette smoke extract (CSE); and (iii) protects against the loss of the ciliated phenotype following long-term CSE exposure.EXPERIMENTAL APPROACHAir-liquid interface cultured human bronchial epithelia…
Discinesia ciliar primaria. Ciliopatías
Resumen La discinesia ciliar primaria es un trastorno geneticamente determinado que se caracteriza por un movimiento ciliar alterado o ausente. Genera un deficit en el aclaramiento mucociliar que se manifiesta clinicamente como infecciones cronicas de vias aereas constantes desde el nacimiento, asi como esterilidad masculina por inmovilidad del espermatozoide y situs inversus en el 40–50% de los pacientes (sindrome de Kartagener). El diagnostico se basa en el estudio de la movilidad ciliar mediante video de alta resolucion digital y alta velocidad, complementado con el estudio de la ultraestructura ciliar. La amplia distribucion ciliar en el organismo y sus numerosas funciones hacen que su …
Perfil farmacológico del roflumilast
Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-n-(3,5-dichloropyrid-4-yl)benzamide) was the first agent of a novel pharmacological class, selective phosphodiesterase 4 (PDE(4)) inhibitors, approved for the use of chronic obstructive pulmonary disease (COPD). The molecular mechanism of action of roflumilast is inhibition of the PDE(4) isoenzyme with a consequent increase of cyclic adenosine monophosphate. Roflumilast evidently has several pharmacological effects: antiinflammatory, anti-emphysema, and antibiotic actions. This drug also inhibits pulmonary hypertension and reduces mucus hypersecretion. The pharmacological actions leading to these effects are: a) inhibition of reactive oxyg…
A Study of the Effect of Proinflammatory Cytokines on the Epithelial Cells of Smokers, With or Without COPD
Introduction: Cigarette smoke is the main cause of inflammation in COPD. The mechanisms that differentiate smokers who develop COPD are diverse. In this study, we analyzed the presence of cytokines in the respiratory secretions of smokers with or without COPD and the secretory properties of the differentiated bronchial epithelium obtained from the individuals themselves after exposure to tobacco smoke. Material and methods: Twenty-seven smokers were studied, 12 of whom had COPD that had not been previously treated with steroids. In 11, samples were obtained by means of induced sputum, and the remaining samples were collected from bronchial aspiration after bronchoscopy. Concentrations of IL…
A preclinical model for skin sensitization prediction of antineoplasic drugs.
e15643 Background: Skin side effects are common manifestations of antineoplastic drugs that are frequently observed in early clinical trials. Therefore, there is a need to identify skin toxic agents before clinical development in order to predict severe skin manifestations. In many cases, skin toxicity is due to sensitization, a key immunologic process mediating redness, swelling and itching that can lead to more severe skin alterations. Methods: We adapted three skin cellular in vitro techniques for cutaneous drug sensitization assessment of the Organization for Economic Cooperation and Development (OECD, 2012) in order to predict antineoplastic drug skin sensitization: 1) Direct peptide …
Estudio del efecto de citocinas proinflamatorias en las células epiteliales de pacientes fumadores con o sin EPOC
Resumen Introduccion El humo de tabaco es la principal causa de la inflamacion en la EPOC. Los mecanismos que diferencian a los fumadores que desarrollan EPOC son diversos. En este estudio analizamos la diferente presencia de citocinas en secreciones respiratorias de pacientes fumadores con o sin EPOC y las propiedades secretoras del epitelio bronquial diferenciado, obtenido de los propios individuos tras su exposicion al humo de tabaco. Material y metodos Se estudio a 27 pacientes fumadores, 12 de ellos con EPOC no tratados previamente con esteroides. En 11 se obtuvo la muestra mediante esputo inducido y el resto procedia del aspirado bronquial tras fibrobroncoscopia. Se determinaron las c…
Primary ciliary dyskinesia. Ciliopathies
Abstract Primary ciliary dyskinesia is a genetically inherited syndrome characterised by ciliary immotility or dysmotility. Deficiency in mucociliary clearance produces chronic respiratory infections from birth, male sterility by spermatozoid immotility and situs inversus in 40%–50% of patients (Kartagener's syndrome). Diagnosis is made by analysing ciliary motility with high-speed digital video and ciliary ultrastructure. The wide distribution and functions of the cilia in the body mean that this dysfunction can generate other ciliopathies apart from primary ciliary dyskinesia.
Inhibidores de fosfodiesterasa 4: un nuevo grupo farmacológico en el tratamiento de la inflamación crónica de las vías aéreas
Los inhibidores de la isoenzima fosfodiesterasa 4 (roflumilast [DAXAS®]) muestran acciones farmacologicas especificas: roflumilast y su metabolito activo (N-oxido roflumilast) producen la inhibicion de la interaccion de los neutrofilos con las celulas endoteliales y, por tanto, disminuyen su extravasacion y muchas de sus funciones, previenen el desarrollo del enfisema inducido por el tabaco en modelos experimentales con animales de investigacion. La modificacion de los diferentes mecanismos que orquestan el agrandamiento y destruccion alveolar, como la acumulacion de celulas inflamatorias en el espacio alveolar, los procesos apoptoticos de las celulas endoteliales y la disminucion del estre…
Mechanisms of skin toxicity of paclitaxel: An in vitro preclinical assessment.
e15511 Background: Paclitaxel skin toxicity is a frequent side effect extensively evaluated in the clinical setting. However little is known about the preclinical mechanisms that lead to this toxicity. The endpoint of this study was to analyse the cutaneous mechanisms that drive paclitaxel toxicity in a preclinical model. Methods: Primary human keratinocytes were co-cultured with human dermal fibroblast in collagen gel under air-liquid interface conditions to generate a multilayered 3D epidermis. Paclitaxel was added to 3D epidermis at 0.3 µM, 3 µM and 30 µM and total RNA and protein was extracted after 24h of incubation. Markers of cell senescence (p21 and p53), anti-apoptotic mediators (…
Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a
Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients’ …