Víctor I Peinado

University of Barcelona, Barcino, Catalonia, Spain

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Publications (55)230.68 Total impact

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    ABSTRACT: Sildenafil, a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension, may have effects on pulmonary vessel structure and function. We evaluated the effects of sildenafil in a cigarette smoke (CS)-exposed model of chronic obstructive pulmonary disease (COPD). 42 guinea-pigs were exposed to cigarette smoke or sham-exposed and treated with sildenafil or vehicle for 12 weeks, divided into four groups. Assessments included respiratory resistance, pulmonary artery pressure (PAP), right ventricle (RV) hypertrophy, endothelial function of the pulmonary artery and lung vessel and parenchymal morphometry. CS-exposed animals showed increased PAP, RV hypertrophy, raised respiratory resistance, airspace enlargement and intrapulmonary vessel remodelling. CS exposure also produced wall thickening, increased contractility and endothelial dysfunction in the main pulmonary artery. CS-exposed animals treated with sildenafil showed lower PAP and a trend to less RV hypertrophy than CS-exposed only animals. Furthermore, sildenafil preserved the intrapulmonary vessel density and attenuated the airspace enlargement induced by CS. No differences in gas exchange, respiratory resistance, endothelial function and vessel remodelling were observed. We conclude that in this experimental model of COPD, sildenafil prevents the development of pulmonary hypertension and contributes to preserve the parenchymal and vascular integrity, reinforcing the notion that the nitric oxide-cyclic guanosine monophosphate axis is perturbed by CS exposure. Copyright ©ERS 2015.
    European Respiratory Journal 04/2015; DOI:10.1183/09031936.00139914 · 7.13 Impact Factor
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    ABSTRACT: Fibronectin (Fn) and tenascin-C (TnC) are two extracellular matrix proteins associated with remodeling changes. Fn and TnC gene and protein expression in lung tissue, including their predominant location in bronchial and pulmonary artery structures, have not yet been fully evaluated. The aim of the present study was to assess: (1) gene expression of Fn and TnC in lung samples from chronic obstructive pulmonary disease (COPD) and non-COPD subjects; and (2) protein content and location of Fn and TnC in both groups. Consecutive subjects requiring lung resection due to lung cancer surgery were included. Lung specimens were examined for gene expression by quantitative real-time PCR (values expressed as fold change ratio). The analysis of their protein content and location was performed by western blot and immunohistochemical studies, respectively. Patients were divided into two cohorts according to COPD status. A total of 41 patients (20 with COPD and 21 without COPD) were included. An enhanced Fn gene expression was observed in the COPD group compared to the non-COPD group (4.73 ± 0.54 vs. 2.65 ± 0.57; P = 0.012), whereas no differences in gene TnC expression were observed (2.91 ± 0.44 vs. 2.60 ± 0.48; P = 0.633). No differences in lung protein content and location were found between groups. Immunohistochemical evaluation showed a predominantly vascular and bronchial location of Fn and TnC in both groups. An enhanced lung gene expression of Fn was observed in COPD subjects compared to non-COPD subjects. No differences were found in Fn protein expression or in TnC gene or protein expression among groups.
    Beiträge zur Klinik der Tuberkulose 03/2015; 193(3). DOI:10.1007/s00408-015-9717-7 · 2.17 Impact Factor
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    ABSTRACT: Background: In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown. Objectives: To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function. Methods: 62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45(+)CD34(+)CD133(+) labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects. Results: Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries. Conclusions: Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.
    PLoS ONE 08/2014; 9(8):e106163. DOI:10.1371/journal.pone.0106163 · 3.23 Impact Factor
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    ABSTRACT: A relatively large percentage of patients with chronic obstructive pulmonary disease (COPD) develop systemic co-morbidities that affect prognosis, among which muscle wasting is particularly debilitating. Despite significant research effort, the pathophysiology of this important extrapulmonary manifestation is still unclear. A key question that remains unanswered is to what extent systemic inflammatory mediators might play a role in this pathology. Cigarette smoke (CS) is the main risk factor for developing COPD and therefore animal models chronically exposed to CS have been proposed for mechanistic studies and biomarker discovery. Although mice have been successfully used as a pre-clinical in vivo model to study the pulmonary effects of acute and chronic CS exposure, data suggest that they may be inadequate models for studying the effects of CS on peripheral muscle function. In contrast, recent findings indicate that the guinea pig model (Cavia porcellus) may better mimic muscle wasting. We have used a systems biology approach to compare the transcriptional profile of hindlimb skeletal muscles from a Guinea pig rodent model exposed to CS and/or chronic hypoxia to COPD patients with muscle wasting. We show that guinea pigs exposed to long-term CS accurately reflect most of the transcriptional changes observed in dysfunctional limb muscle of severe COPD patients when compared to matched controls. Using network inference, we could then show that the expression profile in whole lung of genes encoding for soluble inflammatory mediators is informative of the molecular state of skeletal muscles in the guinea pig smoking model. Finally, we show that CXCL10 and CXCL9, two of the candidate systemic cytokines identified using this pre-clinical model, are indeed detected at significantly higher levels in serum of COPD patients, and that their serum protein level is inversely correlated with the expression of aerobic energy metabolism genes in skeletal muscle. We conclude that CXCL10 and CXCL9 are promising candidate inflammatory signals linked to the regulation of central metabolism genes in skeletal muscles. On a methodological level, our work also shows that a system level analysis of animal models of diseases can be very effective to generate clinically relevant hypothesis.
    Genome Medicine 08/2014; 6(8):59. DOI:10.1186/s13073-014-0059-5 · 4.94 Impact Factor
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    ABSTRACT: Rationale Alveolar type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include the repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Objectives To evaluate surfactant protein restoration after alveolar type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Methods Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar type II cells were obtained from healthy animals and transplanted 14 days after bleomycin instillation. Furthermore, one group transplanted with alveolar macrophages and another treated with surfactant were established to evaluate the specificity of the alveolar type II cell transplantation. The animals were sacrificed at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histological study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. Measurements and Main Results The group with alveolar type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. Conclusion In conclusion, this study shows that one of the mechanisms involved in the beneficial effect of alveolar type II cell transplantation is the restoration of the lung surfactant protein levels, needed for proper respiratory function.
    The Journal of Heart and Lung Transplantation 07/2014; DOI:10.1016/j.healun.2014.03.008 · 5.61 Impact Factor
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available. To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions. Investigations were performed in human lung tissue from COPD patients, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours/day, 5 days/week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from 6 cigarettes/day for 3 months, 5 days/week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time PCR and western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation and apoptosis have been done. The functionally essential sGC β1-subunit was downregulated in COPD patients and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma and inhibited adhesion of CS-stimulated neutrophils. The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.
    American Journal of Respiratory and Critical Care Medicine 04/2014; 189(11). DOI:10.1164/rccm.201311-2037OC · 11.99 Impact Factor
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    ABSTRACT: Little is known about the structure and function relationships of pulmonary vessels in the most severe chronic obstructive pulmonary disease (COPD) spectrum. We investigated morphometric, cellular, and physiologic characteristics of pulmonary arteries from COPD patients undergoing bilateral lung transplant. Seventeen patients with very severe COPD (forced expiratory volume in 1 second, 24% ± 7%) were assessed using inert gas exchange and pulmonary hemodynamics while breathing ambient air and 100% oxygen. Morphometry, in vitro reactivity to hypoxia, and inflammatory cell counts of pulmonary arteries were measured in explanted lungs. Patients had moderate ventilation-perfusion imbalance along with mild release of hypoxic pulmonary vasoconstriction. Mild pulmonary hypertension was observed in 7 patients. Explanted lungs had predominant emphysema with mild small airway involvement. In vitro reactivity was modestly altered, with relatively preserved endothelium-dependent relaxation, and vascular remodelling was discrete, with intense CD8(+) T lymphocytes infiltrate. In vitro reactivity correlated with pulmonary vascular resistance (on ambient air) and oxygen-induced pulmonary artery pressure changes. Patients with pulmonary hypertension had more severe morphologic and physiologic emphysema. In end-stage COPD patients undergoing lung transplant, pulmonary vascular involvement is unexpectedly modest, with low-grade endothelial dysfunction. In this sub-set of COPD patients, pulmonary emphysema may constitute the major determinant of the presence of pulmonary hypertension.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2013; 32(12):1262-1269. DOI:10.1016/j.healun.2013.09.007 · 5.61 Impact Factor
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    ABSTRACT: Patients with chronic obstructive pulmonary disease (COPD) often suffer other concomitant disorders, such as cardiovascular diseases (CVD) and metabolic disorders, that influence significantly (and independently of lung function) their health status and prognosis. Thus, COPD is not a single organ condition and disturbances of a complex network of inter-organ connected responses occur and modulate the natural history of the disease. Here, we propose a novel hypothesis that considers a vascularly connected network with: (1) the lungs, as the main external sensor of the system and a major source of "danger signals"; (2) the endothelium, as an internal sensor of the system (also a potential target tissue); and, (3) two key responding elements, bone marrow and adipose tissue, which produce both inflammatory and repair signals. According to the model, the development of COPD, and associated multimorbidities (here we focus on CVD as an important example), depend on the manner in which the vascular connected network responds, adapts or fails to adapt, (dictated by the genetic and epigenetic background of the individual) to the inhalation of particles and gases, mainly in cigarette smoke. The caveats and limitations of the hypothesis, as well as the experimental and clinical research needed to test and explore the proposed model, are also briefly discussed.
    American Journal of Respiratory and Critical Care Medicine 10/2013; DOI:10.1164/rccm.201308-1404PP · 11.99 Impact Factor
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    ABSTRACT: Long-acting muscarinic antagonists (LAMAs) are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of LAMAs have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. 36 guinea pigs were exposed to CS and 22 sham-exposed, for 24 weeks. Animals were nebulized daily with vehicle, aclidinium 10 or 30 μg/mL, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P=0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth-muscle enlargement in small airways (P=0.001) and tended to reduce airspace enlargement (P=0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P=0.04). We conclude that in guinea pigs chronically exposed to CS, aclidinium has anti-remodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.
    American Journal of Respiratory Cell and Molecular Biology 09/2013; 50(2). DOI:10.1165/rcmb.2013-0117OC · 4.11 Impact Factor
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    ABSTRACT: Abstract Cigarette smoke (CS) induces an inflammatory process in the lung that may underlie the development of chronic obstructive pulmonary disease (COPD). The nature and characteristics of this process have not been fully established in animal models. We aimed to evaluate the pulmonary inflammatory reaction and its involvement in structural changes in guinea pigs chronically exposed to CS. 19 Hartley guinea pigs were exposed to 7 cigarettes/day, during 3 or 6 months. 18 control guinea pigs were sham-exposed. Numbers of neutrophils, macrophages and eosinophils and lymphoid follicles were assessed in different lung structures. Airway and vessel morphometry, alveolar space size and collagen deposition were also quantified. After 6 months of exposure, CS-exposed guinea pigs showed increased numbers of neutrophils, macrophages and eosinophils in the airways, intrapulmonary vessels and alveolar septa, as well as lymphoid follicles. Increased numbers of muscularized intrapulmonary vessels were apparent at 3 months. After 6 months of exposure, the airway wall thickened and the alveolar space size increased. Collagen deposition was also apparent in airway walls and alveolar septa after 6 months' exposure. The magnitude of airway wall-thickening correlated with the number of infiltrating inflammatory cells, and the extension of collagen deposition correlated with alveolar space size. We conclude that in the guinea pig, 6 months of CS exposure induces inflammatory cell infiltrate in lung structures, at an intensity that correlates with airway remodelling. These changes resemble those observed in COPD, thus endorsing the pathogenic role of CS and the usefulness of this animal model for its study.
    COPD Journal of Chronic Obstructive Pulmonary Disease 06/2012; 9(5):473-84. DOI:10.3109/15412555.2012.691999 · 2.62 Impact Factor
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    ABSTRACT: The objective of this study is to analyse the frequency and levels of anti-citrullinated peptide/protein antibodies (ACPA) in the serum of non-rheumatoid arthritis (RA) heavy smokers with and without chronic obstructive pulmonary disease (COPD) and compare them with healthy never smokers and patients with RA. Serum samples of 110 heavy smokers without RA, 209 healthy never smokers and 134 patients with RA were tested for ACPA using a commercial anti-cyclic citrullinated peptide antibodies (CCP2) test and a homemade chimeric fibrin/filaggrin citrullinated synthetic peptide (anti-CFFCP) ELISA test. The frequency of positive results and autoantibody levels were compared between groups. The prevalence of the two types of ACPA was slightly higher in heavy smokers than in never smokers, although the difference was not significant, and significantly lower than in RA patients. The highest prevalence of positive ACPA in heavy smokers was found in subjects with COPD (7.4% of positive anti-CFFCP in patients with COPD in comparison with 2.4% in never smokers: OR 3.26; 95% CI 0.85-12.6, p = 0.089). Mean serum levels of ACPA in heavy smokers were not significantly different from those of never smokers. Heavy smokers with COPD had significantly higher levels of anti-CFFCP than those without COPD, although almost all patients had serum levels below the cut-off values. The prevalence of ACPA in heavy smokers without RA is low, but seems to be higher in heavy smokers with COPD. Larger studies are necessary to confirm these findings and determine the relationship between ACPA and lung disease.
    Clinical Rheumatology 03/2012; 31(7):1047-50. DOI:10.1007/s10067-012-1971-y · 1.77 Impact Factor
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    ABSTRACT: Ventilatory effects of chronic cigarette smoke (CS) alone or associated to chronic hypoxia (CH), as frequently occurs in chronic obstructive pulmonary disease (COPD), remain unknown. We have addressed this problem using whole-body plethysmography in guinea-pigs, common models to study harmful effects of CS on the respiratory system. Breathing frequencies (Bf) in control (2-5 months old) guinea pigs is 90-100 breaths/min, their tidal volume (TV) increased with age but lagged behind body weight gain and, as consequence, their minute volume (MV)/Kg decreased with age. MV did not change by acutely breathing 10% O(2) but doubled while breathing 5% CO(2) in air. Exposure to chronic sustained hypoxia (15 days, 12% O(2), CH) did not elicit ventilatory acclimatization nor adaptation. These findings confirm the unresponsiveness of the guinea pig CB to hypoxia. Exposure to CS (3 months) increased Bf and MV but association with CH blunted CS effects. We conclude that CS and CH association accelerates CS-induced respiratory system damage leading to a hypoventilation that can worsen the ongoing COPD process.
    Advances in Experimental Medicine and Biology 01/2012; 758:325-32. DOI:10.1007/978-94-007-4584-1_44 · 2.01 Impact Factor
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    ABSTRACT: Previously we have reported that association of cigarette smoke (CS) and chronic hypoxia (CH) interact positively to physiopathologically remodel pulmonary circulation. In present study we have exposed guinea pigs to CS smoke (four cigarettes/day; 3 months; CS) and to chronic hypoxia (12% O(2), 15 days; CH) alone or in combination (CSCH animals) and evaluated airways remodeling and resistance assessed as Penh (enhance pause). We measured Penh while animals breathe air, 10% O(2) and 5% CO(2) and found that CS and CH animals have higher Penh than controls; Penh was even larger in CSCH animals. A rough parallelism between Penh and thickness of bronchiolar wall and muscular layer and Goblet cell number was noticed. We conclude that CS and CH association accelerates CS-induced respiratory system damage, evidenced by augmented airway resistance, bronchial wall thickness and muscularization and Goblet cell number. Our findings would suggest that appearance of hypoxia would aggravate any preexisting pulmonary pathology by increasing airways resistance and reactivity.
    Respiratory Physiology & Neurobiology 12/2011; 179(2-3):305-13. DOI:10.1016/j.resp.2011.09.013 · 1.97 Impact Factor
  • Joan Albert Barberà · Víctor I Peinado
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is commonly associated with vascular changes in the pulmonary and systemic circulations. Pulmonary muscular arteries characteristically show intimal hyperplasia, which is produced in part by the proliferation of poorly differentiated smooth muscle cells. The origin of these cells has not been determined. Bone marrow has the capacity to produce and mobilize progenitor cells that may be recruited at sites of vascular damage and contribute to vascular repair through their differentiation into endothelial cells. Nevertheless, under some circumstances bone marrow-derived progenitor cells may migrate into the intima and differentiate into smooth muscle cells. Local factors and cell-to-cell contact are critical in determining the fate of progenitor cells in the vessel wall. Studies assessing the number of circulating bone marrow-derived vascular progenitor cells indicate that COPD is characterized by a reduction in circulating hemopoietic and vascular progenitors. The mechanisms of this reduction have not been elucidated. It has been suggested that this process may lead to reduced vascular repair capacity and increase the risk of cardiovascular complications, which are associated with significant morbidity and mortality in COPD. Further investigation in this field and elucidation of the underlying mechanisms will contribute to a better management of this major complication of COPD.
    Proceedings of the American Thoracic Society 11/2011; 8(6):528-34. DOI:10.1513/pats.201101-010MW
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • J A Barberà · V I Peinado
    European Respiratory Journal 04/2011; 37(4):752-4. DOI:10.1183/09031936.00154610 · 7.13 Impact Factor
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    ABSTRACT: Since human lungs are unlikely to repair or regenerate beyond the cellular level, cell therapy has not previously been considered for chronic irreversible obstructive lung diseases. To explore whether cell therapy can restore lung function, we administered allogenic intratracheal mesenchymal stem cell (MSC) in the trachea of rats with chronic thromboembolic pulmonary hypertension (CTEPH), a disease characterized by single or recurrent pulmonary thromboembolic obliteration and progressive pulmonary vascular remodeling. MSCs were retrieved only in high pressure-exposed lungs recruited via a homing stromal derived factor-1 alpha/CXCR4 pathway. After MSC administration, a marked and long-lasting improvement of all clinical parameters and a significant change of the proteome level were detected. Beside a variation of liver proteome, such as Caspase-3, NF- 〈B, Collagen1A1 and 〈-SMA, we also identified more than 300 resident and nonresident lung proteins, e.g. myosin light chain 3 (P16409) or mitochondrial ATP synthase subunit alpha (P15999). These results suggest that cell therapy restores lung function and the therapeutic effects of MSCs may be related to protein-based tissue reconstituting effects.
    Cell Transplantation 03/2011; 20(10). DOI:10.3727/096368910X557254 · 3.57 Impact Factor

Publication Stats

1k Citations
230.68 Total Impact Points

Institutions

  • 2008–2015
    • University of Barcelona
      • Department of Medicine
      Barcino, Catalonia, Spain
  • 2010–2014
    • Centro de Investigacion Biomédica en Red de Enfermedades Respiratorias
      Bunyola, Balearic Islands, Spain
  • 2002–2014
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
    • Southern Medical Clinic
      San Fernando, City of San Fernando, Trinidad and Tobago
  • 2009–2012
    • Hospital Clínic de Barcelona
      • • Servicio de Neumología
      • • Servicio de Reumatología
      Barcino, Catalonia, Spain
  • 2011
    • Universidad de Valladolid
      Valladolid, Castille and León, Spain