Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury
Authors: Jianxin Sun
Jonathan Li
Zhi Guo
Ulhas P Naik
Dilip Shah
Ross Summer
Caleb B Kallen
Freddy Romero
Journal: American Journal of Respiratory Cell and Molecular Biology (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: acute lung injury; acute respiratory distress syndrome; endoplasmic reticulum stress; obesity; saturated fatty acid.
Affiliations: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center., 2 Department of Obstetrics and Gynecology, and., 3 Cardeza Center for Vascular Biology Research, Thomas Jefferson University, Philadelphia, Pennsylvania.

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 Œ±, 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. 

Retracted: Yes

PubPeer comments:
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 Figures 2H and 3A. Much more similar than expected. https: imgur.com f1Q663R , 
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 The authors have replied that they are intending to publish a correction in a parallel thread: https: pubpeer.com publications 18802B609B1B74B0004D2EB0127488 Could the authors indicate the plan for this paper and reconsider providing uncropped original scans to address these very serious reader concerns? Also it isnu2019t clear that even uncropped images can address the data seemingly appearing in two papers (with transformations illustrated in #2 and #3). , 
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 2020 retraction. https: doi.org 10.1165 rcmb.v63retraction1 This article (1) has been retracted by the authors. It was discovered that the same immunoblot images were used to represent two different experimental conditions. This includes Figure 1D in which a blot of GRP78 is identical to a blot labeled as u03b2-catenin in another paper (2), and Figure 2F in which a blot of GADPH is identical to a portion of a GAPDH image used in that paper (2). In addition, anomalies were identified in the Western blot images in Figures 1D, 2B, 2F, 2H, 3A, 3E, 3F, and 5B. Given that the scientific integrity of this study has been compromised, the authors believe that retraction of this paper is the best course of action. All the authors have agreed to this decision. The authors apologize to the Journal and its readers. 1.tShah D, Romero F, Guo Z, Sun J, Li J, Kallen CB, Naik UP, Summer R. Obesity-induced endoplasmic reticulum stress causes lung endothelial dysfunction and promotes acute lung injury. Am J Respir Cell Mol Biol 2017;57:204u2013215. 2.tShah D, Romero F, Duong M, Wang N, Paudyal B, Suratt BT, Kallen CB, Sun J, Zhu Y, Walsh K, Summer R. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury. Sci Rep 2015;5:11362. , 
 Figure 3. Much more similar than expected after 180 degree rotation.  , 
 This paper has been retracted. , 
 https: retractionwatch.com 2022 02 08 philadelphia-area-lung-researcher-up-to-six-retractions ,