Vesículas extracelulares derivadas de células madre mesenquimales : potencial terapéutico en el daño pulmonar agudo

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Farmacología y Toxicología, leída el 04-05-2022Acute respiratory distress syndrome (ARDS) is a pathology characterized by pulmonary vascular dysfunction, inflammatory phenomena, coagulation disorders and pulmonary oedema leading to alveolar collapse and severe arterial hypoxaemia. Although protective ventilatory and haemodynamic support strategies have improved prognosis, the mortality associated remains high and the discovery of new effective treatments would have a major impact on patient survival. Mesenchymal stem cells (MSCs) have been proposed as a possible therapy in different pathologies due to their low immunogenicity and their ability to repair damage (due to their anti-inflammatory, anti-apoptotic, proangiogenic and anti-fibrotic properties). However, this therapeutic capacity has been shown to be due to the involvement of paracrine mechanisms, such as the release of extracellular vesicles (EVs). Several studies have demonstrated the therapeutic potential of extracellular vesicles in different models of acute lung injury and pulmonary hypertension. In addition, MSCs have been shown to exhibit different responses depending on the environment in which they are found, which has led to a growing interest in the search for strategies to increase their beneficial effects. Among the preconditioning strategies, hypoxia and exposure to TLR3 agonists have been shown to enhance the immunomodulatory and angiogenic capacity of EVs...El síndrome de distrés respiratorio agudo (SDRA) es una patología que se caracteriza por disfunción vascular pulmonar, fenómenos inflamatorios, alteraciones de la coagulación y edema pulmonar que produce colapso alveolar e hipoxemia arterial grave. Aunque las estrategias protectoras de soporte ventilatorio y hemodinámico han permitido mejorar el pronóstico, la mortalidad asociada se mantiene elevada por lo que el descubrimiento de nuevos tratamientos efectivos tendría un gran impacto en la supervivencia de los pacientes. Las células madre mesenquimales (MSCs) se han propuesto como una posible terapia en diferentes patologías debido a su baja inmunogenicidad y a su capacidad de reparar el daño (debido a sus propiedades antiinflamatorias, antiapoptóticas, proangiogénicas y antifibróticas). Sin embargo, se ha demostrado que esta capacidad terapéutica se debe a la participación de mecanismos paracrinos, como puede ser la liberación de vesículas extracelulares (VEs). Varias evidencias han demostrado el potencial terapéutico de las vesículas extracelulares en diferentes modelos de daño pulmonar agudo e hipertensión pulmonar. Además, se ha demostrado que las MSCs presentan diferentes respuestas en función del ambiente en el que se encuentren, por lo que ha crecido el interés en la búsqueda de estrategias para incrementar sus efectos beneficiosos. Dentro de las estrategias de preacondicionamiento la hipoxia y la exposición a agonistas TLR3 han demostrado una mejora de la capacidad inmunomoduladora y angiogénica de las VEs...Fac. de MedicinaTRUEunpu

Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency

Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH

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Depto. de Farmacología y ToxicologíaFac. de MedicinaFALSEsubmitte

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Depto. de Farmacología y ToxicologíaFac. de MedicinaFALSEsubmitte

Total, Bioavailable, and Free Vitamin D Levels and Their Prognostic Value in Pulmonary Arterial Hypertension

Introduction: Epidemiological studies suggest a relationship between vitamin D deficiency and cardiovascular and respiratory diseases. However, whether total, bioavailable, and/or free vitamin D levels have a prognostic role in pulmonary arterial hypertension (PAH) is unknown. We aimed to determine total, bioavailable, and free 25-hydroxy-vitamin D (25(OH)vitD) plasma levels and their prognostic value in PAH patients. Methods: In total, 67 samples of plasma from Spanish patients with idiopathic, heritable, or drug-induced PAH were obtained from the Spanish PH Biobank and compared to a cohort of 100 healthy subjects. Clinical parameters were obtained from the Spanish Registry of PAH (REHAP). Results: Seventy percent of PAH patients had severe vitamin D deficiency (total 25(OH)vitD < 10 ng/mL) and secondary hyperparathyroidism. PAH patients with total 25(OH)vitD plasma above the median of this cohort (7.17 ng/mL) had better functional class and higher 6-min walking distance and TAPSE (tricuspid annular plane systolic excursion). The main outcome measure of survival was significantly increased in these patients (age-adjusted hazard ratio: 5.40 (95% confidence interval: 2.88 to 10.12)). Vitamin D-binding protein (DBP) and albumin plasma levels were downregulated in PAH. Bioavailable 25(OH)vitD was decreased in PAH patients compared to the control cohort. Lower levels of bioavailable 25(OH)vitD (<0.91 ng/mL) were associated with more advanced functional class, lower exercise capacity, and higher risk of mortality. Free 25(OH)vitD did not change in PAH; however, lower free 25(OH)vitD (<1.53 pg/mL) values were also associated with high risk of mortality. Conclusions: Vitamin D deficiency is highly prevalent in PAH, and low levels of total 25(OH)vitD were associated with poor prognosis

Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study an international prospective cohort study

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care. We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care