Webinar Featuring Dr. Patty Lee [August 4, 2022 1:00 PM - August 4, 2022 2:00 PM]

Description

"Vascular Senescence & Senolytics" will feature Dr. Patty Lee from Duke University.

Biography:  
Dr. Lee is a graduate of Brown University’s Program in Liberal Medical Education (PLME) who completed her Internal Medicine internship, residency as well as Pulmonary, Critical Care & Sleep Fellowship at the Johns Hopkins School of Medicine. She started as Instructor, Pulmonary Critical Care at Yale University School of Medicine where she rose through the ranks to Professor of Medicine with tenure before being recruited to Duke as Chief of the Pulmonary, Allergy, Critical Care division in 2019. Currently, Dr. Lee is a Professor of Medicine, Cell Biology and Pathology, a physician-scientist whose work in Lung-Vascular Signal Transduction has established numerous multi-campus collaborations. The Lee Lab has revealed new roles for the innate immune system in regulating lung endothelial host-repair-resilience responses, mechanistically linking innate immunity and cell fate processes specifically in the endothelium, in previously un-recognized ways. Based on paradigm-shifting discovery science the Lee Lab is actively developing novel immune-modulators that they discovered to have unique senolytic properties. These small biologics have immense potential for preventative and therapeutic applications in a range of age-related disorders in which senescence is a critical patho-biologic feature. During Dr. Lee’s recent arrival to Duke, she successfully created and launched 1. a multi-disciplinary U54 SCENT [Senescent Cell Evaluations in Normal Tissues], with a primary focus on lungs, 2. a randomized clinical trial, arguably the first of its scale in health professionals, leveraging digital wearables and machine learning approaches to better identify and define health provider Resilience and Burnout Syndrome, and 3. a newly-funded Pulmonary T32 award – all of which Dr. Lee serves as the Principal and/or Contact Investigator.

Abstract:  
RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by gradual destruction of alveolar architecture and subsequent airflow obstruction. Advancing age and significant exposure to cigarette smoke (CS) are common risk factors, yet the pathologic manifestations of COPD are heterogenous and the biologic risk factors for COPD are unclear. Cellular senescence is important for tissue development and would healing, but accumulating senescent cells is also closely link to the pathogenesis of age-related diseases, including COPD. Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity, cellular homeostasis and survival. We previously reported that circulating MIF was lower in smokers with COPD compared with smokers without COPD. Others have confirmed these findings and correlated decreased MIF protein with greater radiologic/functional evidence of emphysema in patients. However, MIF’s anti-senescence mechanisms in lung endothelium are not fully understood.

METHODS: Gene expression microarray analysis was performed on lung tissue from individuals with/without COPD (n=262), and endothelial cell (Ec) CD74 expression was analyzed in single-cell RNA-seq (control n=19, COPD n=29). CD74 expression was determined by immunohistochemistry in human lung. CS extract (CSE) treated HUVEC along with the following recombinant-MIF (rMIF), MIF-siRNA, neutralizing anti-MIF monoclonal antibody (anti-MIF mAb), MIF098 (MIF antagonist), or MIF20 (MIF agonist). U0126 (ERK inhibitor) was added 1 hour prior to MIF20 treatment. Ec were isolated via MACS sorting. Lentiviral mouse MIF (lenti-M) overexpressing vector was constructed by amplifying the fragments from pcDNA3.1/GS-mMIF. Wild-type (WT) and MIF-KO mice (8-10 weeks old) were intranasally administered lenti-control (lenti-C) or lenti-M. AKR/J mice were exposed to CS (4 months), and MIF20 was administered orally (3 mg/mouse) to mice every day for the final 2 months of CS exposure. Pulmonary function tests were performed by FlexiVent. The research protocols were approved by the Institutional Animal Care and Use Committee of Yale and Duke Universities. Student t-tests and one- or two-way ANOVA were used for statistical analysis.

RESULTS: CD74 expression was increased in COPD patients especially in lung Ec (general capillary; gCap). CSE increased p21 and p16 mRNA expression in HUVEC. This increase was attenuated by rMIF or MIF20, while augmented by anti-MIF mAb or MIF98. CSE increased senescence-associated β-galactosidase (SA-β-gal) activity and MIF20 attenuated it. The protective effect of MIF20 against CS-induced Ec senescence was abolished by ERK signaling inhibitor, U0126. MIF-KO mice showed an upshift of PV loop and increased Ec p21 expression, which were attenuated by restoration of MIF expression via lenti-M. CS induced upshift of PV loop, increased p21 and p16 expression, which were attenuated by MIF20.

CONCLUSIONS: The expression of CD74, the cognate receptor for MIF, was increased in COPD. Senescence was induced in Ec by CS, an important causative factor for COPD. MIF20, a novel small molecule MIF agonist, attenuated CS-induced senescence via ERK signaling, which is known to support cell survival and proliferation. We also found MIF expressing lentiviral vectors reduce markers of endothelial senescence in MIF-KO mice. Furthermore, MIF20 prevented CS-induced lung emphysema. These data suggest that therapeutic modulation of MIF targeting in lung Ec is feasible and represents a novel strategy to protect against senescence-induced COPD.