The processes of angiogenesis and lymph-angiogenesis are recognized to play critical roles in cancer progression, metastasis, and many chronic diseases, but also serve non-pathological roles in the normal progression and resolution of inflammation. During inflammation, functioning lymphatics are believed to reduce edema and to provide a transiting route for immune cells; but whether extensive dermal lymphatic remodeling that presumably takes place in inflamed tissue directly impacts transport remains unclear.
To investigate the role of lymphatic function in acute inflammation, we induced acute CHS reactions in normal mice and longitudinally imaged the dermal lymphatics afferent, and the contractile, conducting lymphatics efferent to the regional draining lymph node using NIRF lymphatic imaging. We evaluated the population of cells in inflamed skin, using flow cytometry and histology, as a function of time after induction of acute CHS reaction and assessed lymphatic endothelial cell (LEC) proliferation using a method of incorporation to directly assess proliferation quantitatively. We also assessed the tissue protein expression of growth factors associated to angiogenesis, lymphangiogenesis, and inflammation.
Results show that the LECs proliferate in early onset of CHS, but that this proliferation is not sustained from day 4 to 7 post-CHS. We also determined that the efferent lymph transport is impaired in early CHS as shown by a reduction in lymph ejection, but not by a reduction in lymphatic vessel contractility in both the inflamed and contralateral untreated sides of animals. We then identified several growth factors and inflammatory molecules to be differentially expressed in early inflammation as compared to non-treated animals and animals at later stages of the CHS reaction. VEGF-C and VEGF-D expression were not significantly changed during the course of the CHS reaction. These data may indicate that multiple growth factors other than VEGF-C and VEGF-D work in concordance with VEGF family to promote LECs proliferation, regression, and mediate lymph flow for resolution of CHS inflammation.
Article was published in PlosOne