Modulating Lung Fibroblast Activation via Senolysis of Senescent Human Alveolar Epithelial Cells

BUFFALO, NY- July 17, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 13, entitled, “Modulating in vitro lung fibroblast activation via senolysis of senescent human alveolar epithelial cells.” Idiopathic pulmonary fibrosis (IPF) is an age-related disease with poor prognosis and limited therapeutic options. Activation of lung fibroblasts and differentiation to myofibroblasts are the principal effectors of disease pathology, but damage and senescence of alveolar epithelial cells, specifically type II (ATII) cells, has recently been identified as a potential trigger event for the progressive disease cycle. Targeting ATII senescence and the senescence-associated secretory phenotype (SASP) is an attractive therapeutic strategy; however, translatable primary human cell models that enable mechanistic studies and drug development are lacking. In this new study, researchers Joseph S. Spina, Tracy L. Carr, Lucy A. Phillips, Heather L. Knight, Nancy E. Crosbie, Sarah M. Lloyd, Manisha A. Jhala, Tony J. Lam, Jozsef Karman, Meghan E. Clements, Tovah A. Day, Justin D. Crane, and William J. Housley from AbbVie Bioresearch Center and Northeastern University describe a novel system of conditioned medium (CM) transfer from bleomycin-induced senescent primary alveolar epithelial cells (AEC) onto normal human lung fibroblasts (NHLF) that demonstrates an enhanced fibrotic transcriptional and secretory phenotype compared to non-senescent AEC CM treatment or direct bleomycin damage of the NHLFs. “In the current study, we confirm the presence of senescent cell populations within the human IPF lung, as well as assess primary cell reagents for sensitivity to senescent cell targeting therapies.” In this system, the bleomycin-treated AECs exhibited classical hallmarks of cellular senescence, including SASP and a gene expression profile that resembles aberrant epithelial cells of the IPF lung. Fibroblast activation by CM transfer was attenuated by pre-treatment of senescent AECs with the senolytic Navitoclax and AD80, but not with the standard of care agent Nintedanib or senomorphic JAK-targeting drugs (e.g., ABT-317, ruxolitinib). This model provided a relevant human system for profiling novel senescence-targeting therapeutics for IPF drug development. “Taken together, the model described herein provides a physiologically relevant, primary human cell system to study the effects of alveolar epithelial cell senescence on lung fibroblasts in the context of chronic fibrotic lung disease.” DOI - https://doi.org/10.18632/aging.205994 Corresponding author - Tovah A. Day - t.day@northeastern.edu Video short - https://www.youtube.com/watch?v=rpmo2PlGDKc Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205994 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM