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P016. Stimulation of lymphatic function via VEGFR‑3 as a novel therapy for chronic experimental intestinal inflammation

S. D'Alessio1, C. Correale1, V. Arena2, S. Danese1

1Istituto Clinico Humanitas, Rozzano, Italy; 2Catholic University of Rome, Internal Medicine Department/Gastroenterology Division, Rome, Italy

Background: In both forms of inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), submucosal edema, extensive dilation of lacteals, lymphocytic thrombi within lymphatics, and lymphocyte aggregates often containing granulomas suggest the existence of poor lymph drainage secondary to either lymphatic obstruction or impaired contractile function of the mesenteric lymphatic vessels. In addition, increased lymphangiogenesis has been described in IBD. However, whether this intense lymphangiogenesis is initially an appropriate and beneficial adaptation that ultimately becomes dysregulated due to the chronicity of inflammation, or is abnormal from the onset of disease remains to be established.

Methods: We addressed these issues in vivo by systemic inhibition of VEGFR‑3 and delivery of the lymphangiogenic factor VEGF‑C in the dextran sulfate sodium (DSS) model of colitis by a blocking antibody or adenovirus transfer respectively. Whole mount of proximal and distal colons were stained during acute and chronic colitis with antibodies against LYVE‑1 and CD31 to measure area density and dimension of lymphatic vessels. Lymphatic drainage was assessed by intramucosal injection of Evans blue dye. Moreover, in vitro tubulogenesis was used to assess human intestinal lymphatic endothelial cells (HILEC) organization into capillary tubules within a 3D environment.

Results: Despite the enhanced lymphangiogenesis, lymph flow was highly reduced during DSS-induced colitis (p < 0.001), particularly in chronic DSS colitis. Systemic inhibition of VEGFR‑3 blocked lymphangiogenesis, reducing area density (from 35±0.8 to 14±0.3 vessels/mm2, p < 0.01) and lymphatic vessel dimension (from 81±1.4 µm to 39±0.9 µm, p < 0.01), while significantly increased inflammatory edema formation and inhibited (p < 0.001) disease resolution, assessed as body weight loss, colitis activity Index and histological score. Vice versa, although lymphatic drainage was inhibited in the chronic phase of colitis, it was enhanced by systemic delivery of the lymphangiogenic factor VEGF‑C, which in turn significantly improved colitis both clinically and histologically.

Conclusions: Our findings demonstrate that stimulation of functional lymphangiogenesis via VEGFR‑3 accelerates disease resolution and inhibits chronic inflammation. Correction of defective lymphatic function may therefore offer an entirely novel therapeutic strategy for IBD.