Mechanisms of Junctional Proteins in Post-Surgical Lymphedema

Lymphedema is chronic limb swelling from lymphatic dysfunction which affects 250 million people worldwide. It is estimated that 5-10 million Americans have lymphedema. Primary lymphedema is rare and results from errors in lymphatic development. Secondary lymphedema accounts for 99% of the condition and occurs most commonly following surgical management of solid tumors (e.g., breast cancer, melanoma). Axillary lymph node dissection results in lymphedema in 30% of patients post-operatively. Skin thickening, interstitial fluid retention, and fibroadipose subcutaneous deposition from inflammation result in progressive limb enlargement. Lymphedema impacts quality of life and has a high health cost burden. Morbidity includes recurrent cellulitis, pain, and impaired extremity function. Non-surgical management of lymphedema includes compression therapy. Surgical treatment involves excisional (e.g, skin/subcutaneous resection) and microsurgical physiologic procedures including vascularized lymph node transfer and lymphovenous bypass. Current treatments may variably improve limb size, but do not cure lymphedema. Lymphatic capillaries develop discontinuous button-like junctional proteins which facilitate absorption of interstitial fluid into lymphatics at the capillary level. Continuous zipper-like junctional proteins are present in lymphatics which transport lymph without leakage. Rare genetic causes of primary lymphedema affect initial lymphatic capillary button junction development resulting in zippers instead of buttons. In the lung, chronic pleural inflammation has been found to result in the replacement of button junctions in pleural lymphatics with zipper junctions leading to impaired drainage function and pleural effusion. Secondary lymphedema occurs on an average of one year post-operatively following surgical lymph node dissection indicating the etiology of lymphedema is not only the mechanical disruption of lymphatics. Following post-surgical lymphatic injury, activation and maintenance of chronic inflammation is critical in the development of lymphedema. The goal of this application is to understand the mechanism and pathophysiology of junctional protein changes in secondary lymphedema. This will inform us about the fundamental underlying etiology of lymphatic stasis in lymphedema and, importantly, help us develop targeted therapies to improve the lives of patients with lymphedema. We hypothesize that inflammation after lymphatic injury results in capillary lymphatic button junction changes to impermeable zipper junctions rendering interstitial fluid uptake inefficient. In Aim 1, we elucidate how lymphatic injury affects lymphatic junctional proteins in secondary lymphedema. In Aim 2, we determine the effects gene delivery targeting junctional protein pathways following lymphatic injury. Our approach uses a combination of mouse models and clinical specimen to have a high translational significance. Project Number: 1R01HL180721-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Aladdin Hassanein | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $414,996 | Activity Code: R01 | Study Section: Surgery, Anesthesiology and Trauma Study Section[SAT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18072101