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Chronic Wounds Cause Localized Lymphatic Dysfunction
Jeremy S. Torrisi, B.A., Ira L. Savetsky, M.D., Jason C. Gardenier, M.D., Gabriela D. Garcia Nores, M.D., Matthew D. Nitti, B.A., Geoffrey E. Hespe, B.S., Raghu P. Kataru, Ph.D, Babak J. Mehrara, M.D..
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Chronic wounds are a major cause of morbidity and a significant source of biomedical expenditures in the United States. Previous studies have focused upon studying the association between angiogenesis and wound closure because chronic wounds have been shown to have profound circulatory defects. In contrast, the role of the lymphatic system in chronic wound healing remains poorly understood. This concept is important to study as the profound fibrosis, inflammation and edema caused by chronic wounds is histologically similar to what is seen in lymphedema. Therefore, the goal of this study was to examine lymphatic function in peri-chronic wound regions. Furthermore, this study examined whether augmenting lymphatic function could be a viable new method for treating patients who are suffering from chronic wounds.
We modified a model of chronic wound healing in C57BL6/J mice that enabled us to analyze in vivo lymphatic function as wound healing occurred. We removed a 5 mm semi-circumferential portion of tail skin located 2 cm away from the tail base while preserving the deep lymphatic collectors and lateral tail veins. Wound closure and lymphatic function were analyzed weekly after surgery using histology, FITC dextran lymphangiography, and immunohistochemistry. In separate animals, we analyzed the effects of neutralizing antibodies against IL-4 and IL-13 on the rate of chronic wound healing since we have shown previously that this treatment enhances lymphatic function.
Similar to the clinical scenario, we found that the tail wounds healed primarily by epithelialization over a period of 3-4 weeks. Analysis of lymphatic function in the peri-wound areas both proximal and distal to the wound demonstrated impaired lymphatic function and decreased uptake of lymphatic-specific FITC dextran injected in the distal tail. The regions of lymphatic dysfunction around the wound were 3-4 times the size of the wound crater at any given time point. These changes improved as the wound healed but persisted even 6 weeks into wound healing. Peri-wound histological analysis demonstrated chronic inflammation and edema. Interestingly, we found that wounds had a primarily CD4+ inflammatory response that increased until the wound fully healed, and that these cells were primarily T-helper 2 (Th2) differentiated. These findings correlate with the inflammation seen in lymphedema. Treatment with antibodies against Th2 cytokines IL-4 and IL-13 markedly accelerated wound closure, increased lymphangiogenesis, and decreased peri-wound inflammation.
We have shown that chronic wounds cause regions of lymphatic dysfunction in peri-wound areas, with regions of dysfunction significantly larger than the wound ulcer. We have also found that inflammation around the wound was reminiscent of the CD4+ Th2 inflammation seen in lymphedema. Interestingly, wounds healed faster when Th2 differentiation was inhibited using anti-IL-4 and anti-IL-13 antibodies. These findings provide a new avenue for treatment of chronic wounds, as augmenting lymphatic function through inhibition of Th2 differentiation could help to promote wound healing in patients with chronic wounds.

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