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

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Lymphatic Dysfunction Amplifies the Pathological Effects of Obesity in Skin Inflammation
Ira L. Savetsky, MD, Nicholas J. Albano, BS, Jason C. Gardenier, MD, Jeremy S. Torrisi, BA, Gabriela D. Garcia Nores, MD, Matthew D. Nitti, BA, Geoffrey E. Hespe, BS, Raghu P. Kataru, PhD, Babak J. Mehrara, MD FACS.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: We have previously shown that obesity markedly impairs lymphatic function. Given that the lymphatic system is a critical physiologic regulator of inflammatory responses, a key mechanism by which the negative effects of obesity are exerted, we have hypothesized that obesity-induced lymphatic dysfunction acts in a feed forward manner to increase obesity-induced inflammation and thereby amplify the pathology of obesity. To test this hypothesis, we used a model of atopic dermatitis since previous studies have shown that obesity is a significant risk factor for this disease.
Methods: We used a model of atopic dermatitis in mice that had been made obese by feeding a high fat diet (DIO) or maintained lean by feeding a normal chow diet. In this model, the animals were exposed to a sensitizing agent (DNFB; topical application to the ear) followed by elicitation of skin inflammation with repeat exposure. Lymphatic function and skin inflammation were measured and correlated with obesity. To test the hypothesis that improving lymphatic function in obese mice can decrease pathologic outcomes of atopic dermatitis, we injected recombinant human vascular endothelial growth factor-C (rhVEGF-C) into ears of DIO mice before sensitization with DNFB and measured pathological outcomes.
Results: Consistent with our previous studies, we found that obese mice had significantly impaired lymphatic function with leakiness of initial lymphatics, decreased pumping capacity of collecting lymphatics, and abnormalities in peripheral lymph node architecture. Obese mice also had significantly increased peak inflammatory responses to DNFB as compared with controls. Consistent with atopic dermatitis, these responses were associated with increased T cell inflammation and increased interferon gamma expression (P<0.05 for both). In addition, obese mice required significantly longer time periods to clear inflammatory responses as compared with lean mice suggesting that obesity not only increases the intensity of inflammation but, more importantly, impairs its resolution. Injection of rhVEGF-C did not cause weight loss or changes in the metabolic profile, however this treatment was associated with a marked lymphangiogenic response and improved local lymphatic function in obese mice. This effect was also associated with marked decreases in peak inflammation and clearance of inflammatory responses to DNFB suggesting that improved lymphatic function in obesity decreases the pathological outcomes of obesity in atopic dermatitis.
Conclusions: This study provides substantial evidence supporting the hypothesis that lymphatic dysfunction is a critical mechanism regulating inflammatory responses in diet-induced obesity. We have shown that modulation of lymphatic function in obese animals using lymphangiogenic growth factors markedly decreases inflammatory responses and decreases the pathologic effects of obesity in a mouse model of atopic dermatitis. This suggests that modulation of lymphatic function may be a novel means of treating obesity-associated diseases.


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