title: Endotoxin-induced lung alveolar cell injury causes brain cell damage.
abstract: Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain Critical Patient Translational Research Group, Department of Anesthesiology, Intensive Care and Pain Management, Hospital Clínico Universitario, Instituto de Investigación Sanitaria (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, 15706, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodríguez-González
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Ramos-Nuez
authors.affiliation: Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain Animal Facility Service, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martín-Barrasa
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain Critical Care Center, Corporació Sanitaria Parc Taulí, Sabadell, 08208 Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: López-Aguilar
authors.affiliation: Critical Patient Translational Research Group, Department of Anesthesiology, Intensive Care and Pain Management, Hospital Clínico Universitario, Instituto de Investigación Sanitaria (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, 15706, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Baluja
authors.affiliation: Critical Patient Translational Research Group, Department of Anesthesiology, Intensive Care and Pain Management, Hospital Clínico Universitario, Instituto de Investigación Sanitaria (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, 15706, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Álvarez
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil.
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, 16126 Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pelosi
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain Li Ka Shing Knowledge Institute at the St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada jesus.villar54@gmail.com.
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects*; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004731:Endotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D008962:Models, Theoretical; D009474:Neurons / Q000187:drug effects*; D011650:Pulmonary Alveoli / Q000187:drug effects*; D017207:Rats, Sprague-Dawley
chemical_list: D017077:Culture Media, Conditioned; D004731:Endotoxins
keywords: Sepsis; acute respiratory distress syndrome; apoptosis; brain injury; inflammation; lung injury