Pain during photodynamic therapy (PDT) is the main limiting adverse effect in its use in dermatology. Given its multifactorial nature, we reviewed both intrinsic and extrinsic factors that are involved in PDT pain. We propose a threshold theory for pain experience in PDT: it correlates positively with fluence rate and dose below a certain threshold (rate of ~60 mW cm , dose of ~50 J cm ); when the threshold is surpassed, pain intensity saturates. Additionally, we carefully compared recent updates on pain management strategies and we suggest that cold-air analgesia and low-irradiance light sources (such as variable pulsed light and daylight PDT) represent the current best analgesic options. Finally, we discuss the possible mechanisms of pain experience during PDT. Reactive oxygen species, transient receptor potential channels and inflammatory responses are key mediators in pain. Further investigation into these pathways should help with the development of more effective analgesic strategies. Taking these points together, for pain management in PDT, an individualized plan of analgesia is possible.

Angiogenesis and lymphangiogenesis are thought to play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, it is not understood if inflammatory lymphangiogenesis is a pathological consequence or a productive attempt to resolve the inflammation. This study investigated the effect of lymphangiogenesis on intestinal inflammation by overexpressing a lymphangiogenesis factor, vascular endothelial growth factor-C (VEGF-C), in a mouse model of acute colitis. Forty eight-week-old female C57BL/6 mice were treated with recombinant adenovirus overexpressing VEGF-C or with recombinant VEGF-C156S protein. Acute colitis was then established by exposing the mice to 5% dextran sodium sulfate (DSS) for 7 days. Mice were evaluated for disease activity index (DAI), colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), and VEGFR-3mRNA expression in colon tissue. When acute colitis was induced in mice overexpressing VEGF-C, there was a significant increase in colonic epithelial damage, inflammatory edema, microvessel density, and neutrophil infiltration compared to control mice. These mice also exhibited increased lymphatic vessel density (73.0±3.9 vs 38.2±1.9, P<0.001) and lymphatic vessel size (1974.6±104.3 vs 1639.0±91.5, P<0.001) compared to control mice. Additionally, the expression of VEGFR-3 mRNA was significantly upregulated in VEGF-C156S mice compared to DSS-treated mice after induction of colitis (42.0±1.4 vs 3.5±0.4, P<0.001). Stimulation of lymphangiogenesis by VEGF-C during acute colitis promoted inflammatory lymphangiogenesis in the colon and aggravated intestinal inflammation. Inflammatory lymphangiogenesis may have pleiotropic effects at different stages of IBD.

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