Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Chronic Wounds have Surrounding Regions of Lymphatic Dysfunction
Jeremy S. Torrisi, BA, Ira L. Savetsky, MD, Jason C. Gardenier, MD, Gabriela Garcia Nores, MD, Matthew D. Nitti, BA, Geoffrey E. Hespe, BS, Raghu Kataru, Ph.D, Babak J. Mehrara, MD, FACS.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PURPOSE:Chronic wounds are a significant source of biomedical expenditures and a major cause of morbidity in the United States. Based on the fact that patients with chronic wounds tend to have circulatory defects, the vast majority of chronic wound studies have focused on the association between angiogenesis and wound closure. In contrast, there is little known about the role of lymphatic vessel formation and function in chronic wounds. This gap in our knowledge is important since histological changes in the tissues surrounding chronic wounds (i.e. fibrosis, inflammation, edema) are reminiscent of biopsy specimens from lymphedematous limbs. Therefore, the purposes of this study were to analyze lymphatic function in the regions surrounding chronic wounds and determine if improving lymphatic function increases the rate of wound closure.
METHODS: We developed a model of chronic wound healing in C57BL6/J mice that enabled us to analyze lymphatic function concurrently with wound closure. We removed a 5 mm semi-circumferential portion of the tail skin at a point located 2 cm away from the base while preserving the deep collectors and lateral tail veins. Wound closure and lymphatic function were analyzed 0, 2, 4, and 6 weeks after surgery using histology, indocyanine green (ICG) lymphangiography, and immunohistochemistry. In separate animals, we analyzed the effects of neutralizing antibodies against IL-4 and IL-13 on the rate of wound closure since we have previously shown that this treatment improves lymphatic function.
RESULTS: Due to the fibrous connection of the tail skin, we found that similar to the clinical scenario, 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 ICG injected in the distal tail. The regions of lymphatic dysfunction around the wound were 3-4 times the size of the actual wound at any given time point. However, although evidence of lymphatic dysfunction persisted even at the 6 week time point, these changes were noted to improve over time. Histological analysis of the wound and surrounding regions demonstrated significant fibrosis and chronic inflammation. Similar to our previous studies in lymphedema, we found that the vast majority of inflammatory cells present in the peri-wound regions of specimens harvested 2-6 weeks after surgery were CD4+ cells with evidence of T-helper 2 (Th2) differentiation. Furthermore, treatment of animals with antibodies against IL-4 and IL-13 markedly accelerated wound closure, increased lymphangiogenesis, and improved peri-wound lymphatic function.
CONCLUSION: We have shown that chronic wounds are associated with regions of lymphatic dysfunction in the peri-wound areas. In addition, we have shown that these regions of lymphatic dysfunction are significantly larger than the area of the actual wound ulcer. We found that inflammatory changes in the regions surrounding the open wound were consistent with lymphedema demonstrating CD4+ cell inflammatory infiltrate and Th2 differentiation. Finally, we have shown that inhibition of these inflammatory responses not only improves lymphangiogenesis and lymphatic function, but also markedly accelerates wound closure.


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