title: Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates.
abstract: Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome (ARDS). Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide (LPS)-induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS. Human alveolar A549 and human bronchial BEAS-2B cells were exposed to LPS, either alone or in combination with the pyrrol derivatives. Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA0118 had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. Exposure to LPS caused an intense inflammatory response and apoptosis in both A549 and BEAS-2B cells. DTA0118 treatment downregulated Toll-like receptor-4 expression and upregulated nuclear factor-κB inhibitor-α expression in cells exposed to LPS. These anti-inflammatory effects were accompanied by a significantly lower secretion of interleukin-6 (IL-6), IL-8, and IL-1β. The observed antiapoptotic effect of DTA0118 was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels. Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA0118 compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.|Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Cabrera-Benítez
authors.affiliation: BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' IUBO-AG, Centro de Investigaciones Biomédicas de Canarias, Universidad de La Laguna, La Laguna, Tenerife, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Roth
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.|Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Ramos-Nuez
authors.affiliation: Department of Immunology, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain.
authors.forename: Ithaisa
authors.initials: I
authors.lastname: Sologuren
authors.affiliation: BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' IUBO-AG, Centro de Investigaciones Biomédicas de Canarias, Universidad de La Laguna, La Laguna, Tenerife, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Padrón
authors.affiliation: Keenan Research Center for Biomedical Science, St Michael´s Hospital, Toronto, ON, Canada.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.|Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain.|Keenan Research Center for Biomedical Science, St Michael´s Hospital, Toronto, ON, Canada.
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
mesh_terms: D000072283:A549 Cells; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000209:etiology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D018805:Sepsis / Q000150:complications; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C494826:BAX protein, human; D016207:Cytokines; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051028:bcl-2-Associated X Protein; D000072000:NF-KappaB Inhibitor alpha; C505407:CASP3 protein, human; D053148:Caspase 3