title: Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.
abstract: RETRACTED: Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese individuals.
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Dilip
authors.initials: D
authors.lastname: Shah
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Freddy
authors.initials: F
authors.lastname: Romero
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Guo
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Li
authors.affiliation: 2 Department of Obstetrics and Gynecology, and.
authors.forename: Caleb B
authors.initials: CB
authors.lastname: Kallen
authors.affiliation: 3 Cardeza Center for Vascular Biology Research, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ulhas P
authors.initials: UP
authors.lastname: Naik
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Ross
authors.initials: R
authors.lastname: Summer
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D055371:Acute Lung Injury / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004041:Dietary Fats / Q000627:therapeutic use / Q000633:toxicity; D004198:Disease Susceptibility; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005227:Fatty Acids / Q000097:blood* / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D009765:Obesity / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D010654:Phenylbutyrates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044967:Serum; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D015815:Cell Adhesion Molecules; D004041:Dietary Fats; D004722:Endoribonucleases; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D005230:Fatty Acids, Nonesterified; D008070:Lipopolysaccharides; D010654:Phenylbutyrates; D017346:Protein Serine-Threonine Kinases; D014415:Tunicamycin; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C075773:4-phenylbutyric acid; C510185:Ern1 protein, mouse
keywords: acute lung injury; acute respiratory distress syndrome; endoplasmic reticulum stress; obesity; saturated fatty acid