SUMMARY

The lymphatic vasculature exists in nearly all tissues of the body and plays essential roles in maintaining fluid balance through fluid and protein clearance of the interstitium, in immune cell trafficking, and in lipid transport. Despite the critical functions that the lymphatics perform, relatively little is known about their role in disease progression. Lymphatic involvement has been demonstrated in many highly prevalent diseases such as congestive heart failure, atherosclerosis, metabolic syndrome, inflammatory diseases, and cancer, but one of the strongest associations with the onset of lymphatic dysfunction is obesity. Recently, obesity via chronic inflammation has been correlated with development of primary and secondary lymphedemas, incurable conditions caused by impaired lymphatic drainage. Although it remains unclear how obesity may compromise collecting lymphatic pump function and whether the molecular mechanisms involved in this process would produce new opportunities for therapeutic intervention. Further, it is unknown how inflammation may exacerbate development of secondary lymphedema in cases where the lymphatic vasculature undergoes physical insult and subsequent remodeling. This is of particular clinical importance because obesity is one of the few identifiable risk factors known to increase lymphedema risk. This information is essential to understanding the pathological spectrum of lymphatic dysfunction. Our central hypothesis is that inflammation adversely affects lymphatic pump function, decreasing lymph transport, and subsequently leading to lymphedema. This project aims to investigate the role of chronic and acute inflammation in exacerbating lymphedema development by its effects potential lymphatic failure modes. To this end, we have developed and validated novel near-infrared (NIR) imaging methodologies for non-invasively phenotyping lymphatic disease over the course of lymphedema progression. We are proposing to utilize these methodologies to assess the effects of chronic and acute inflammation during lymphedema on lymphatic function in both mice and sheep. The significance of this work is to parse out the lymphatic transport modalities that are adversely affected by inflammation. This is essential for determining the molecular mechanisms involved in these processes, and subsequently identifying therapeutic targets for restoring lymphatic function in the presence of lymphedema.