The Impact of Anesthetics on Lymphatic Vessel Contractility and Extracellular Fluid Uptake

Project Summary / Abstract The lymphatic system, integral to fluid balance, fat absorption, and immunity, actively propels lymph fluid via specialized lymphatic muscle cells (LMCs) and coordinated contractile behavior. Lymphatic vessels play a crucial role in maintaining fluid balance. The entire plasma volume extravasates from the blood roughly every 9 hours

and is reclaimed by the lymphatic system and returned to the central circulation. Disruption to lymphatic function, from factors like inflammation or medications, can lead to edema. In critical illness, edema increases morbidity and mortality. Despite extensive use of anesthetics like isoflurane, propofol, ketamine, and dexmedetomidine,

their impact on lymphatic function remains unknown. In this innovative proposal, the goal is to study the impact of these anesthetics on lymphatic function using advanced lymphatic functional imaging techniques in a novel murine model of critical care. The translational model includes tracheostomy, controlled mechanical ventilation,

an intra-arterial line, a central venous catheter for infusion of drugs, and vital sign monitoring. This is combined with three imaging modalities: intravital fluorescence lymphangiography to quantitatively measure lymphatic contractions, intravital near infrared fluorescence lymphangiography to measure lymphatic network behavior,

and a novel bioluminescent assay to quantify the rate of clearance of interstitial fluid. In Aim 1, experiments will probe the effects of various anesthetics on lymphatic contractility in a critical care mouse model. Both systemic influences and direct vascular effects of anesthetics on lymphatic function and fluid clearance will be measured.

Electrophysiology will complement in vivo lymphatic imaging to directly observe changes in LMC excitability mediated by anesthetics. In Aim 2, the study will explore the relationship between anesthetics and lymphatic adrenergic receptor activation, examining whether anesthetics influence lymphatic contractility via the

sympathetic nervous system, the potential functional rescue effects of norepinephrine, and the distribution of adrenergic receptors in human lymphatic tissue. The proposed research aspires to profoundly shape future clinical practice by elucidating the impact of anesthetics on lymphatic pumping and tissue edema. This will allow

for future tailored anesthetic selection in the operating room and intensive care unit based on the patient’s level of edema. The Mentored Clinical Scientist Research Career Development Award candidate, an MD, PhD with a research background in electrophysiology and lymphatics, serves as an anesthesiologist and intensivist at

Massachusetts General Hospital and is dedicated to advancing an academic trajectory in translational research. An expert mentorship team in lymphatic imaging (Dr. Padera, PhD), instrumented mouse models (Dr. Ichinose, MD, PhD), and electrophysiology (Dr. Logothetis, PhD) will help the candidate combine these unique areas to

achieve the proposal aims. Through the guidance of trailblazing basic scientists and clinicians, with training courses in an exceptionally resource-rich environment at Harvard Medical School, she is poised to acquire the skills necessary to lead an independent laboratory performing pioneering critical care and lymphatic research.