Therapeutic effects of soluble guanylate cyclase stimulation on pulmonary hemodynamics and emphysema development in guinea pigs chronically exposed to cigarette smoke.

We have analyzed the effect of the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 in a therapeutic intervention in guinea pigs chronically exposed to cigarette smoke (CS). The effects of sGC stimulation on respiratory function, pulmonary hemodynamics, airspace size, vessel remodeling, and inflammatory cell recruitment to the lungs were evaluated in animals that had been exposed to CS for 3 mo. CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half. Animals that stopped CS exposure had slightly lower pulmonary artery pressure (PAP) and right ventricle (RV) hypertrophy than those who continued CS exposure, but they did not recover from the emphysema and the inflammatory cell infiltrate. Conversely, oral BAY 41-2272 administration stopped progression or even reversed the CS-induced emphysema in both current and former smokers, respectively. Furthermore, BAY 41-2272 produced a reduction in the RV hypertrophy, which correlated with a decrease in the PAP values. By contrast, the degree of vessel remodeling induced by CS remained unchanged in the treated animals. Functional network analysis suggested perforin/granzyme pathway downregulation as an action mechanism capable of stopping the progression of emphysema after sGC stimulation. The pathway analysis also showed normalization of the expression of cGMP-dependent serine/kinases. In conclusion, in guinea pigs chronically exposed to CS, sGC stimulation exerts beneficial effects on the lung parenchyma and the pulmonary vasculature, suggesting that sGC stimulators might be a potential alternative for chronic obstructive pulmonary disease treatment that deserves further evaluation.

Progenitor cell mobilisation and recruitment in pulmonary arteries in chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction. METHODS: Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45+ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively. RESULTS: COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45+ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = - 0.35, p < 0.05). In pulmonary arteries, the number of CD45+ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = - 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels. CONCLUSION: In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD.

Imbalance between endothelial damage and repair capacity in chronic obstructive pulmonary disease.

BACKGROUND: Circulating endothelial microparticles (EMPs) and progenitor cells (PCs) are biological markers of endothelial function and endogenous repair capacity. The study was aimed to investigate whether COPD patients have an imbalance between EMPs to PCs compared to controls and to evaluate the effect of cigarette smoke on these circulating markers. METHODS: Circulating EMPs and PCs were determined by flow cytometry in 27 nonsmokers, 20 smokers and 61 COPD patients with moderate to severe airflow obstruction. We compared total EMPs (CD31+CD42b-), apoptotic if they co-expressed Annexin-V+ or activated if they co-expressed CD62E+, circulating PCs (CD34+CD133+CD45+) and the EMPs/PCs ratio between groups. RESULTS: COPD patients presented increased levels of total and apoptotic circulating EMPs, and an increased EMPs/PCs ratio, compared with nonsmokers. Women had less circulating PCs than men through all groups and those with COPD showed lower levels of PCs than both control groups. In smokers, circulating EMPs and PCs did not differ from nonsmokers, being the EMPs/PCs ratio in an intermediate position between COPD and nonsmokers. CONCLUSIONS: We conclude that COPD patients present an imbalance between endothelial damage and repair capacity that might explain the frequent concurrence of cardiovascular disorders. Factors related to the disease itself and gender, rather than cigarette smoking, may account for this imbalance.

Gene expression profile of angiogenic factors in pulmonary arteries in COPD: relationship with vascular remodeling.

Pulmonary vessel remodeling in chronic obstructive pulmonary disease (COPD) involves changes in smooth muscle cell proliferation, which are highly dependent on the coordinated interaction of angiogenic-related growth factors. The purpose of the study was to investigate, in isolated pulmonary arteries (PA) from patients with COPD, the gene expression of 46 genes known to be modulators of the angiogenic process and/or involved in smooth muscle cell proliferation and to relate it to vascular remodeling. PA segments were isolated from 29 patients and classified into tertiles, according to intimal thickness. After RNA extraction, the gene expression was assessed by RT-PCR using TaqMan low-density arrays. The univariate analysis only showed upregulation of angiopoietin-2 (ANGPT-2) in remodeled PA (P < 0.05). The immunohistochemical expression of ANGPT-2 correlated with intimal enlargement (r = 0.42, P < 0.05). However, a combination of 10 factors in a multivariate discriminant analysis model explained up to 96% of the classification of the arteries. A network analysis of 46 genes showed major decentralization. In this network, the metalloproteinase-2 (MMP-2) was shown to be the bridge between intimal enlargement and fibrogenic factors. In COPD patients, plasma levels of ANGPT-2 were higher in current smokers or those with pulmonary hypertension. We conclude that an imbalance in ANGPT-2, combined with related factors such as VEGF, ß-catenin, and MMP-2, may partially explain the structural derangements of the arterial wall. MMP-2 may act as a bridge channeling actions from the main fibrogenic factors.

Ingesta de fruita dels nens i nenes en edat escolar / Ingesta de fruta de los niños y niñas en edad escolar / Fruit intake by school-age children

Fonament: el consum de fruita recomanat en l'edat escolarés de dues a tres racions al dia. Objectiu: conèixer el consum de fruita dels pacients de 3 a14 anys visitats en la nostra consulta d'atenció primària. Investigar alguns factors que podrien influir en la seva ingesta. Mètode: estudi observacional transversal mitjançant enquesta única sobre el consum de fruita de l'infant. Descripció de freqüències relatives (%) o mitjanes (DE) de lesvariables següents: edat, nombre de racions i tipus de fruitaque van menjar el dia anterior a la visita, en els momentssegüents: esmorzar (casa i escola), dinar (casa i/o escola), berenar, sopar i altres. Analitzar la relació entre el nombrede racions de fruita que menja un infant segons l'edat, lapoblació on viu i el nivell d'estudis dels pares. Resultats: s'analitza la ingesta de fruita durant el curs esco-lar 2011-12 de 778 infants entre 3 i 14 anys (mitjana 7,27anys). La majoria consumeixen entre una i dues racions aldia (1,89 racions/dia) amb les excepcions dels infants de 10 anys (2,2) i els de 14 anys (1,7). Els infants que viuenfora de la província de Barcelona i els fills de mares universitàries són els que van menjar més fruita. Les tres fruitesmés consumides van ser el plàtan, la poma i la pera. Conclusions: la majoria d'infants enquestats mengenmenys de 2 racions de fruita al dia (1,89 racions/dia), perla qual cosa hem de continuar fomentant-ne el consumdiari, així com aconseguir diversificar-ne els tipus

Introducción. El consumo de fruta recomendado en la edad escolar es de dos a tres raciones al día. Objetivo. Conocer el consumo de fruta de los pacientes de 3 a 14 años visitados en nuestra consulta de atención primaria. Investigar algunos factores que podrían influir en su consumo. Mètode. Estudio observacional transversal mediante una encuesta única sobre el consumo de fruta del niño el día anterior a la visita. Descripción de frecuencias relativas (%) o medias (DE) de las siguientes variables: edad, número de raciones y tipo de fruta que comieron el día anterior de la visita en los siguientes momentos: desayuno (casa y colegio), comida (casa y/o colegio), merienda, cena y en otros momentos del día. Analizar la relación entre el número de raciones de fruta que come un niño en función de su edad, la población donde vive y el nivel de estudios de los padres. Resultados. Se analiza la ingestión de fruta durante el curso escolar 2011-2012 de 778 niños entre 3 y 14 años (mediana 7,27 años). La mayoría de niños consumieron entre una y dos raciones al día (1,89 raciones/día) con la excepción de los niños de 10 años (2,2) y los de 14 años (1,7). Los niños que viven fuera de la provincia de Barcelona y los hijos de madres universitarias fueron los que comieron más fruta. Las tres frutas preferentes son el plátano, la manzana y la pera. Conclusiones. El consumo de fruta recomendado en la edad escolar es de dos a tres raciones al día. La mayoría de niños encuestados comen menos (1,89 raciones/día), por lo que tenemos que seguir fomentando el consumo de fruta en diferentes momentos del día, así como conseguir diversificar los tipos de fruta (AU)

Background. The recommended daily intake of fruit for school-age children is two to three servings. Objective. To describe the fruit intake by children between 3 and 14 years of age attending our primary clinic and to determine factors that could influence it. Methods. Cross-sectional study, using a single survey on fruit consumption the day before the visit. The following variables were collected: age, type and number of servings of fruit taken the day before the visit, at the following times: breakfast (home and school), lunch (home or school), snack, dinner, and other times in the day. We analyzed the relationship between the number of servings of fruit the children ate and the age, the area where they reside, and the educational level of their parents. Results. During the 2011-2012 school year a total of 778 children between 3 and 14 years (mean 7.27 years) were included in this study. Most children had one or two servings per day (median 1.89 servings/day); the highest intake was among 10-year-old children (2.2 servings/day) and the lowest was among 14-year-old adolescents (1.7 servings/day). Children residing outside the province of Barcelona and children whose mothers have a University degree ate more fruit servings. The three most commonly consumed fruits were bananas, apples, and pears. Conclusions. The children surveyed ate fewer than the 2-3 servings of fruit per day recommended in school-age children. The consumption of fruit at different times of the day and the diversification of the fruit offered should be encouraged (AU)

Retorno venoso pulmonar total anómalo en pediatría: importancia del diagnóstico ecocardiográfico y de la cirugía precoz / Total anomalous pulmonary venous connection in the pediatric age:iImportance of echocardiographic diagnosis and early repair

Introducción y objetivos. Estudiamos los pacientes afectados de retorno venoso pulmonar total anómalo intervenidos en nuestro centro. Presentamos la importancia del diagnóstico ecocardiográfico exclusivo previo a la cirugía. Métodos. Desde 1990 hasta 1999, 14 pacientes fueron intervenidos de dicha cardiopatía en nuestro centro. El sitio de drenaje fue en 6 pacientes supracardíaco, 4 infracardíaco, 1 cardíaco (seno coronario) y en 3 pacientes mixto. En 11 casos el diagnóstico se realizó por estudio ecocardiográfico, siendo los hallazgos corroborados durante la cirugía. Resultados. Sólo hubo una muerte durante la intervención quirúrgica, relacionada con un ventrículo izquierdo pequeño, y a los 35 días de la intervención se produjo otro fallecimiento por sepsis. Durante el postoperatorio inmediato, el control y tratamiento de la hipertensión pulmonar fueron los objetivos primordiales. Tras un seguimiento medio de 50 meses, sólo un paciente precisó reintervención; el resto de pacientes se encuentra asintomático. Conclusiones. El diagnóstico ecocardiográfico de esta cardiopatía puede ser suficiente para indicar la cirugía. Así mismo la corrección quirúrgica precoz del retorno venoso pulmonar anómalo total puede ser realizada con bajo riesgo y buenos resultados a medio plazo (AU)