Abstract Submissions are Opened | Early Bird Registration Closes on August 15, 2022 |
Senescence of alveolar type II (ATII) cells, progenitors of the alveolar epithelium, is a pathological feature and is believed to contribute importantly to the initiation and progression of idiopathic pulmonary fibrosis (IPF), an aging-related progressive fatal lung disorder with unknown etiology and no effective treatment. The mechanism underlying ATII cell senescence and by which senescent ATII cells contribute to lung fibrogenesis, however, remains poorly understood. Our recent studies showed that ATII cells in IPF lungs expressed higher levels of plasminogen activator inhibitor 1 (PAI 1), a serine protease inhibitor that plays a critical role in fibrinolysis and the development of lung fibrosis, and cell cycle repressors p21 and p16, compared to ATII cells in control lungs. Both bleomycin and transforming growth factor beta1 (TGF-1), two lung fibrosis inducers, induced PAI-1 and ATII cell senescence in vitro and in vivo. Using pharmacological and genetic approaches as well as an ATII cell specific PAI-1 conditional knockout (CKO) mouse model we showed that PAI-1 mediated, at least in part, bleomycin-induced ATII cell senescence through activating p53-p21-pRb cell cycle repression pathway but TGF-1-induced ATII cell senescence through upregulating p16-pRb pathway in vitro and in vivo. We also showed that the conditional medium from senescent ATII cells promoted the transition of fibrogenic phenotype of alveolar macrophages. Deletion or inhibition of PAI-1 in ATII cells almost completely blocked the stimulatory effects of the conditional medium from senescent ATII cells on macrophages. Coordinately, ablation of PAI-1 specifically in ATII cells in mice attenuated bleomycin-induced lung fibrosis. Our new studies further show that PAI-1 mediates bleomycin-induced A549 cell senescence through binding to 20S of proteasome and inhibits proteasome activity and thus p53 degradation. As PAI-1 expression is increased in IPF lung, our data suggest that increased PAI-1 may underlie ATII cell senescence in IPF lung. Our studies also reveal a novel mechanism whereby PAI-1 promotes ATII cell senescence. That is binding to proteasome components and inhibiting proteasome activity and thus p53 degradation.
Audience Take Away:
I am a tenured Professor at the Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham. My research focuses on oxidative stress/antioxidants, aging, and aging related diseases, including idiopathic pulmonary fibrosis (IPF). I have obtained numerous grants from different funding agencies including National Institute of Health (NIH), American Lung Association, and Department of Defense (DOD) to study the etiology and pathogenesis of IPF as well as explore the therapeutic drugs for IPF. I have published 80 peer-reviewed papers in the field.