RT Journal Article
SR Electronic
T1 The Self-fulfilling Prophecy of Pulmonary Fibrosis: A Selective Inspection of Pathologic Signaling Loops
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2000075
DO 10.1183/13993003.00075-2020
A1 Ashley R. Rackow
A1 David J. Nagel
A1 Claire McCarthy
A1 Jennifer Judge
A1 Shannon Lacy
A1 Margaret A. T. Freeberg
A1 Thomas H. Thatcher
A1 R. Matthew Kottmann
A1 Patricia J. Sime
YR 2020
UL http://erj.ersjournals.com/content/early/2020/07/06/13993003.00075-2020.abstract
AB Pulmonary fibrosis is a devastating, progressive disease and carries a prognosis worse than most cancers. Despite ongoing research, the mechanism(s) which underlie disease pathogenesis remain only partially understood. However, the self-perpetuating nature of pulmonary fibrosis has led several researchers to propose the existence of pathologic signaling loops. According to this hypothesis, the normal wound healing process becomes corrupted and results in the progressive accumulation of scar tissue in the lung. In addition, several negative regulators of pulmonary fibrosis are downregulated and therefore are no longer capable of inhibiting these feed-forward loops. Thus, the combination of pathologic signaling loops and loss of a checks and balances system ultimately culminates in a process of unregulated scar formation. This review details specific feed forward loops demonstrated to play a role in the pathogenesis of pulmonary fibrosis. The evidence of detrimental signaling loops is elucidated with regard to epithelial cell injury, cellular senescence, and the activation of developmental and aging pathways. We demonstrate where these feed-forward loops intersect each other, as well as common mediators which may drive these responses and how the loss of pro-resolving mediators may contribute to the propagation of disease. By focusing on the overlapping signaling mediators among the many pro-fibrotic pathways, it is our hope that the pulmonary fibrosis community will be better equipped to design future trials that incorporate the redundant nature of these pathways as we move toward finding a cure for this unrelenting disease.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Ms. Rackow has nothing to disclose.Conflict of interest: Dr. Nagel reports grants from National Heart, Lung, and Blood Institution, during the conduct of the study.Conflict of interest: Dr. McCarthy has nothing to disclose.Conflict of interest: Dr. Judge has nothing to disclose.Conflict of interest: Dr. Lacy is employed by the U.S. Army. The views expressed herein are those of the author and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government..Conflict of interest: Dr. Thatcher reports grants from NIH, during the conduct of the study.Conflict of interest: Dr. Kottmann reports grants from National Institutes of Health, during the conduct of the study; In addition, Dr. Kottmann has a patent LDH inhibitors as treatment for fibrosis and fibrotic-related disorders issued.Conflict of interest: Dr. Sime reports grants from NIH, during the conduct of the study; grants from NIH, grants and personal fees from UCB, personal fees from Boehringer Ingelheim, personal fees from Intermune/Roche, personal fees from GSK, personal fees from Prometic, personal fees from Galecto, other from Guy Solimano and Greg Chandler Fund, outside the submitted work; In addition, Dr. Sime has a patent Methods of Diagnosing and Treating Fibrosis issued, a patent LDH Inhibitors as Treatment for Fibrosis and Fibrotic-Related Disorders issued, and a patent A method and apparatus to diagnose metastatic and progressive potential of cancer, fibrosis and other diseases pending.Conflict of interest: Dr. Thomas Freeberg has nothing to disclose.