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Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder for which there are two FDA-approved anti-fibrotic drugs, nintedanib, and pirfenidone. While these drugs slow the rate of decline in lung function, responses are variable and side effects are common. Using an in-silico data-driven approach, we identified a strong inverse connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor, originally developed for oncological indications. Accordingly, we investigated the anti-fibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: (i) in vitro in normal human lung fibroblasts (NHLFs); (ii) in vivo in bleomycin and recombinant adenovirus transforming growth factor-beta (Ad-TGF-β) murine models of pulmonary fibrosis; and (iii) ex vivo in mice and human precision cut lung slices from these two murine models as well as from patients with IPF and healthy donors. In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-β-stimulated NHLFs identified specific gene sets associated with fibrosis including epithelial mesenchymal transition (EMT), TGF-β, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways including EMT, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
Biography
Dr. Downey received his MD from the University of Manitoba and completed Internship and Residency in Internal Medicine at Harvard Medical School, Beth Israel and Brigham and Women’s Hospital, Boston. He then completed clinical training in Pulmonary and Critical Care Medicine at the University of Colorado, Denver. He undertook post-doctoral research training in Immunology in the laboratory of Dr. Peter Henson at National Jewish Health. He was appointed Assistant Professor at the University of Toronto rising through the ranks to become the Director of the Division of Respirology, Professor and Vice-Chair, Department of Medicine, and the recipient of a Tier 1 Canada Research Chair in Respiration Sciences. Dr. Downey returned to Colorado as Executive Vice President of Academic Affairs and Provost and Professor of Medicine, Pediatrics, and Immunology and Genomic Medicine at National Jewish Health, and Professor of Medicine and Immunology and Microbiology and Associate Dean of the School of Medicine, University of Colorado. His current research interests include innate immunity, signaling mechanisms involved in acute lung injury/ARDS, the effects of particulate matter exposure on lung health, and mechanisms and treatment of pulmonary fibrosis. His research has been funded by the National Institutes of Health, the Canadian Institutes of Health Research, and the US Department of Defense for over 30 years. Dr. Downey has >250 publications in top ranked journals including the New England Journal of Medicine, Science, Science Translational Medicine, Nature Cell Biology, the Journal of Cell Biology, the American Journal of Respiratory and Critical Care Medicine, the Journal of Experimental Medicine, Blood, PNAS, the American Journal of Respiratory Cell and Molecular Biology, and the Journal of Immunology and his work has been cited over 23,000 times by other authors (h-index 83). Dr. Downey is a member of the American Society for Clinical Investigation, the Association of American Physicians, the American Thoracic Society, the American College of Chest Physicians, the Royal College of Physicians and Surgeons of Canada. He currently serves as the Immediate Past President of the American Thoracic Society.