Examinando por Autor "Tapia, Pablo"
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Ítem Correction for Echeverría et al., "Endotoxin-Induced Endothelial Fibrosis Is Dependent on Expression of Transforming Growth Factors β1 and β2" [Infect Immun., Volume 82, no. 9, p. 3678-3686, 2014](American Society for Microbiology, 2015) Echeverría, César; Montorfano, Ignacio; Tapia, Pablo; Riedel, Claudia; Cabello-Verrugio, Claudio; Simon, Felipe aÍtem Disseminated intravascular coagulation phenotype is regulated by the TRPM7 channel during sepsis(2023-12) Jiménez‑Dinamarca, Ivanka; Prado, Yolanda; Tapia, Pablo; Gatica, Sebastian; Alt, Clemens; P. Lin, Charles; Martínez, Cristian Reyes; G. Feijóo, Carmen; Aravena, Cristobal; González‑Canace, Alejandra; Correa, Simón; Varela, Diego; Cabello‑Verrugio, Claudio; Simon, FelipeBackground: Sepsis is an uncontrolled inflammatory response against a systemic infection that results in elevated mortality, mainly induced by bacterial products known as endotoxins, producing endotoxemia. Disseminated intravascular coagulation (DIC) is frequently observed in septic patients and is associated with organ failure and death. Sepsis activates endothelial cells (ECs), promoting a prothrombotic phenotype contributing to DIC. Ion channel-mediated calcium permeability participates in coagulation. The transient reception potential melastatin 7 (TRPM7) non-selective divalent cation channel that also contains an α-kinase domain, which is permeable to divalent cations including Ca2+, regulates endotoxin-stimulated calcium permeability in ECs and is associated with increased mortality in septic patients. However, whether endothelial TRPM7 mediates endotoxemia-induced coagulation is not known. Therefore, our aim was to examine if TRPM7 mediates coagulation during endotoxemia. Results: The results showed that TRPM7 regulated endotoxin-induced platelet and neutrophil adhesion to ECs, dependent on the TRPM7 ion channel activity and by the α-kinase function. Endotoxic animals showed that TRPM7 mediated neutrophil rolling on blood vessels and intravascular coagulation. TRPM7 mediated the increased expression of the adhesion proteins, von Willebrand factor (vWF), intercellular adhesion molecule 1 (ICAM-1), and P-selectin, which were also mediated by the TRPM7 α-kinase function. Notably, endotoxin-induced expression of vWF, ICAM-1 and P-selectin were required for endotoxin-induced platelet and neutrophil adhesion to ECs. Endotoxemic rats showed increased endothelial TRPM7 expression associated with a procoagulant phenotype, liver and kidney dysfunction, increased death events and an increased relative risk of death. Interestingly, circulating ECs (CECs) from septic shock patients (SSPs) showed increased TRPM7 expression associated with increased DIC scores and decreased survival times. Additionally, SSPs with a high expression of TRPM7 in CECs showed increased mortality and relative risk of death. Notably, CECs from SSPs showed significant results from the AUROC analyses for predicting mortality in SSPs that were better than the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores. Conclusions: Our study demonstrates that sepsis-induced DIC is mediated by TRPM7 in ECs. TRPM7 ion channel activity and α-kinase function are required by DIC-mediated sepsis-induced organ dysfunction and its expression are associated with increased mortality during sepsis. TRPM7 appears as a new prognostic biomarker to predict mortality associated to DIC in SSPs, and as a novel target for drug development against DIC during infectious inflammatory diseases. © 2023, The Author(s).Ítem Endotoxin-induced endothelial fibrosis is dependent on expression of transforming growth factors β1 and β2(American Society for Microbiology, 2014) Echeverría, César; Montorfano, Ignacio; Tapia, Pablo; Riedel, Claudia; Cabello-Verrugio, Claudio; Simon, FelipeDuring endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endo thelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expres sion pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic in ducers are transforming growth factor 1 (TGF- 1) and TGF- 2. However, whether TGF- 1 and TGF- 2 participate in endo toxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF- receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus sug gesting that endotoxin elicits TGF- production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF- 1 and TGF- 2. Endotoxin-treated ECs induced the expression and secretion of TGF- 1 and TGF- 2. TGF- 1 and TGF- 2 downregulation inhibited the endotoxin induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins -SMA and fibronectin. Thus, endotoxin in duces the production of TGF- 1 and TGF- 2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF- secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotox in-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseasesÍtem Extracorporeal membrane oxygenation improves survival in a novel 24-hour pig model of severe acute respiratory distress syndrome(E-CENTURY PUBLISHING CORP, 2016-06) Araos, Joaquín; Alegría, Leyla; García, Patricio; Damiani, Felipe; Tapia, Pablo; Soto, Dagoberto; Salomon, Tatiana; Rodriguez, Felipe; Amthauer, Macarena; Erranz, Benjamín; Castro, Gabriel; Carreño, Pamela; Medina, Tania; Retamal, Jaime; Cruces, Pablo; Bugedo, Guillermo; Bruhn, AlejandroExtracorporeal membrane oxygenation (ECMO) is increasingly being used to treat severe acute respiratory distress syndrome (ARDS). However, there is limited clinical evidence about how to optimize the technique. Experimental research can provide an alternative to fill the actual knowledge gap. The purpose of the present study was to develop and validate an animal model of acute lung injury (ALI) which resembled severe ARDS, and which could be successfully supported with ECMO. Eighteen pigs were randomly allocated into three groups: sham, ALI, and ALI + ECMO. ALI was induced by a double-hit consisting in repeated saline lavage followed by a 2-hour period of injurious ventilation. All animals were followed up to 24 hours while being ventilated with conventional ventilation (tidal volume 10 ml/kg). The lung injury model resulted in severe hypoxemia, increased airway pressures, pulmonary hypertension, and altered alveolar membrane barrier function, as indicated by an increased protein concentration in bronchoalveolar fluid, and increased wet/dry lung weight ratio. Histologic examination revealed severe diffuse alveolar damage, characteristic of ARDS. Veno-venous ECMO was started at the end of lung injury induction with a flow > 60 ml/kg/min resulting in rapid reversal of hypoxemia and pulmonary hypertension. Mortality was 0, 66.6 and 16.6% in the SHAM, ALI and ALI + ECMO groups, respectively (p < 0.05). This is a novel clinically relevant animal model that can be used to optimize the approach to ECMO and foster translational research in extracorporeal lung support.Ítem Oxidized High-Density Lipoprotein Induces Endothelial Fibrosis Promoting Hyperpermeability, Hypotension, and Increased Mortality(Antioxidants, 2022) Rojas, Macarena; Prado, Yolanda; Tapia, Pablo; Carreño, Leandro J.; Cabello-Verrugio, Claudio; Simon, FelipeDuring systemic inflammation, reactive oxygen species (ROS) are generated in the blood-stream, producing large amounts of oxidized HDL (oxHDL). OxHDL loses the vascular protective features of native HDL, acquiring detrimental actions. Systemic inflammation promotes endothelial fibrosis, characterized by adhesion protein downregulation and fibrotic-specific gene upregulation, disrupting endothelial monolayer integrity. Severe systemic inflammatory conditions, as found in critically ill patients in the intensive care unit (ICU), exhibit endothelial hyperpermeability, hypoten sion, and organ hypoperfusion, promoting organ dysfunction and increased mortality. Because endothelial fibrosis disturbs the endothelium, it is proposed that it is the cellular and molecular origin of endothelial hyperpermeability and the subsequent deleterious consequences. However, whether oxHDL is involved in this process is unknown. The aim of this study was to investigate the fibrotic effect of oxHDL on the endothelium, to elucidate the underlying molecular and cellular mechanism, and to determine its effects on vascular permeability, blood pressure, and mortality. The results showed that oxHDL induces endothelial fibrosis through the LOX-1/NOX-2/ROS/NF-κB pathway, TGF-β secretion, and ALK-5/Smad activation. OxHDL-treated rats showed endothelial hyperpermeability, hypotension, and an enhanced risk of death and mortality, which was prevented using an ALK-5 inhibitor and antioxidant diet consumption. Additionally, the ICU patients showed fibrotic endothelial cells, and the resuscitation fluid volume administered correlated with the plasma oxHDL levels associated with an elevated risk of death and mortality. We conclude that oxHDL generates endothelial fibrosis, impacting blood pressure regulation and survival.Ítem Relaciones entre calidad de vida y Burnout en terapeutas ocupacionales de la Región Metropolitana durante el año 2012(Universidad Andrés Bello, 2013) Durán Hernández, David; Zapata Campos, Felipe; Tapia, Pablo; Facultad de Ciencias de la Rehabilitación; Escuela Terapia OcupacionalEl presente estudio aborda las relaciones entre la calidad de vida y el síndrome de Burnout en terapeutas ocupacionales de la Región Metropolitana de Santiago, que se desempeñan en instituciones públicas y privadas hace más de 6 meses, al año 2012. La investigación se desarrolló desde un enfoque cuantitativo, de tipo de diseño no experimental, producción de datos transversal y alcance correlaciona!. Utilizamos como método de recolección y producción de datos: el WHOQOL-BREF para la medición de la calidad de vida y el test MBI-HSS para la medición del síndrome de Burnout, instrumentos válidos y con tradición de uso dentro del país para la medición de nuestros constructos. Los análisis de datos, desde el nivel descriptivo al comparativo y correlaciona! se realizaron con el software estadístico SSPS 19 por su adecuación a modelos de análisis cuantitativos en ciencias sociales. Para nuestra pregunta de investigación ¿Cómo se relaciona la calidad de vida y el puntaje de Burnout en terapeutas ocupacionales de la Región Metropolitana que se desempeñen en instituciones públicas y privadas por más de 6 meses, en el año 2012?. Para responder nuestra pregunta de investigación, primero obtuvimos datos sociodemográficos que dieran cuenta de la realidad actual de los terapeutas ocupacionales en la región metropolitana. Luego analizar la muestra con ambos instrumentos por separado y describir los datos obtenidos. En seguida cruzar las variables de cada instrumento y observar si se correlacionan entre sí y para finalizar confeccionar perfiles de riesgo de síndrome de Burnout. En los resultados obtenidos constatamos que la calidad de vida tiene directa relación con el posible desarrollo de síndrome de Burnout, es decir a mayor puntaje en calidad de vida menor probabilidad de desarrollar síndrome de Burnout, asimismo a la inversa menor puntaje en calidad de vida mayor riesgo de padecer síndrome de Burnout.Ítem Sepsis-Induced Coagulopathy Phenotype Induced by Oxidized High-Density Lipoprotein Associated with Increased Mortality in Septic-Shock Patients(MDPI, 2023-02) Prado, Yolanda; Tapia, Pablo; Eltit, Felipe; Reyes-Martínez, Cristian; Feijóo, Carmen G.; Llancalahuen, Felipe M.; Riedel, Claudia A.; Cabello-Verrugio, Claudio; Stehberg, Jimmy; Simon, FelipeSepsis syndrome is a highly lethal uncontrolled response to an infection, which is characterized by sepsis-induced coagulopathy (SIC). High-density lipoprotein (HDL) exhibits antithrombotic activity, regulating coagulation in vascular endothelial cells. Sepsis induces the release of several proinflammatory molecules, including reactive oxygen species, which lead to an increase in oxidative stress in blood vessels. Thus, circulating lipoproteins, such as HDL, are oxidized to oxHDL, which promotes hemostatic dysfunction, acquiring prothrombotic properties linked to the severity of organ failure in septic-shock patients (SSP). However, a rigorous and comprehensive investigation demonstrating that oxHDL is associated with a coagulopathy-associated deleterious outcome of SSP, has not been reported. Thus, we investigated the participation of plasma oxHDL in coagulopathy-associated sepsis pathogenesis and elucidated the underlying molecular mechanism. A prospective study was conducted on 42 patients admitted to intensive care units, (26 SSP and 16 non-SSP) and 39 healthy volunteers. We found that an increased plasma oxHDL level in SSP was associated with a prothrombotic phenotype, increased mortality and elevated risk of death, which predicts mortality in SSP. The underlying mechanism indicates that oxHDL triggers an endothelial protein expression reprogramming of coagulation factors and procoagulant adhesion proteins, to produce a prothrombotic environment, mainly mediated by the endothelial LOX-1 receptor. Our study demonstrates that an increased plasma oxHDL level is associated with coagulopathy in SSP through a mechanism involving the endothelial LOX-1 receptor and endothelial protein expression regulation. Therefore, the plasma oxHDL level plays a role in the molecular mechanism associated with increased mortality in SSP. © 2023 by the authors.