Lipid Synthesis Is Required to Resolve Endoplasmic Reticulum Stress and Limit Fibrotic Responses in the Lung
Authors: Clementina Mesaros
Jan B Hoek
DeLeila Schriner
Nathaniel W Snyder
Zhi Guo
Hoora Shaghaghi
Augustine M Choi
Xu Hong
Dilip Shah
Ross Summer
Julie Barta
Caleb B Kallen
Ivan Rosas
Freddy Romero
Journal: American Journal of Respiratory Cell and Molecular Biology (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: alveolar epithelium; endoplasmic reticulum stress; lipid synthesis; pulmonary fibrosis; unfolded protein response.
Affiliations: 1 Center for Translational Medicine., 2 Jane and Leonard Korman Lung Center., 3 Medical Research Center, North China University of Science and Technology, Tangshan, China., 4 Department of Obstetrics and Gynecology, and., 5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., 6 Department of Pulmonary Diseases, Jinan Military General Hospital, Jinan, China., 7 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania., 8 University of Pennsylvania Superfund Research and Training Program (Penn SRP) Center and Center of Excellence in Environmental Toxicology, and., 9 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., 10 Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York; and., 11 A. J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania.

Abstract:  Endoplasmic reticulum (ER) stress is evident in the alveolar epithelium of humans and mice with pulmonary fibrosis, but neither the mechanisms causing ER stress nor the contribution of ER stress to fibrosis is understood. A well-recognized adaptive response to ER stress is that affected cells induce lipid synthesis; however, we recently reported that lipid synthesis was downregulated in the alveolar epithelium in pulmonary fibrosis. In the present study, we sought to determine whether lipid synthesis is needed to resolve ER stress and limit fibrotic remodeling in the lung. Pharmacologic and genetic manipulations were performed to assess whether lipid production is required for resolving ER stress and limiting fibrotic responses in cultured alveolar epithelial cells and whole-lung tissues. Concentrations of ER stress markers and lipid synthesis enzymes were also measured in control and idiopathic pulmonary fibrosis lung tissues. We found that chemical agents that induce ER stress (tunicamycin or thapsigargin) enhanced lipid production in cultured alveolar epithelial cells and in the mouse lung. Moreover, lipid production was found to be dependent on the enzyme stearoyl-coenzyme A desaturase 1, and when pharmacologically inhibited, ER stress persisted and lung fibrosis ensued. Conversely, lipid production was reduced in mouse and human fibrotic lung, despite there being an increase in the magnitude of ER stress. Furthermore, augmenting lipid production effectively reduced ER stress and mitigated fibrotic remodeling in the mouse lung after exposure to silica. Augmenting lipid production reduces ER stress and attenuates fibrotic remodeling in the mouse lung, suggesting that similar approaches might be effective for treating human fibrotic lung diseases. 

Retracted: No

PubPeer comments:
 Figure 7D. Much more similar than expected. https: imgur.com LZ0FBB2 , 
 Figure 7D. Different number lanes. https: imgur.com nohDasO , 
 Figure 7D. Much more similar than expected. https: imgur.com 3f4R8yG , 
 Figures 5A and 7D. eIf2 panels very similar, although the treatments are different. https: imgur.com mhK8XMA , 
 Figure 6. * Pink boxes: Six lanes in the GAPDH panels of Figure 6A and Figure 6D look similar to each other. ![file] ,