Abstract
Impaired wound healing is an ongoing issue that cancer patients undergoing chemotherapy or radiotherapy face. Our previous study regarding lung-cancer-associated pleural fluid (LCPF) demonstrated its propensity to promote endothelial proliferation, migration, and angiogenesis, which are crucial features during cutaneous wound healing. Therefore, the current study aimed to investigate the effect of pleural fluid on cutaneous wound closure in vitro and in vivo using HaCaT keratinocytes and a full-thickness skin wound model, respectively. Both heart-failure-associated pleural fluid (HFPF) and LCPF were sequentially centrifuged and filtered to obtain a cell-free status. Treatment with HFPF and LCPF homogeneously induced HaCaT proliferation with cell cycle progression, migration, and MMP2 upregulation. Western blotting revealed increased PI3K/Akt phosphorylation and VEGFR2/VEGFA expression in HaCaT cells. When treated with the PI3K inhibitor, LCPF-induced keratinocyte proliferation was attenuated with decreased pS6 levels. By applying the VEGFR2 inhibitor, LCPF-induced keratinocyte proliferation was ameliorated by pS6 and MMP2 downregulation. The effect of LCPF-induced cell junction rearrangement was disrupted by co-treatment with a VEGFR2 inhibitor. Compared with a 0.9% saline dressing, LCPF significantly accelerated wound closure and re-epithelization when used as a dressing material in a full-thickness wound model. Histological analysis revealed increased neo-epidermis thickness and dermis collagen synthesis in the LCPF-treated group. Furthermore, LCPF treatment activated basal keratinocytes at the wound edge with the upregulation of Ki-67, VEGFA, and MMP2. Our preliminaries provided the benefit of wet dressing with pleural fluid to improve cutaneous wound closure through enhanced re-epithelization and disclosed future autologous application in cancer wound treatment.
Highlights
Multiple growth factors are involved in cutaneous wound healing through the promotion of the proliferation and migration of resident cells [1]
Numergrowth factors were involved in cutaneous wound healing, such as VEGF, bFGF, and ous growth factors were involved in cutaneous wound healing, such as VEGF, bFGF, and hepatocyte growth factor (HGF)
The current study investigated the potential of cell-free pleural fluid in vitro and in vivo using keratinocytes and a full-thickness skin wound model, respectively (Figure 10)
Summary
Multiple growth factors are involved in cutaneous wound healing through the promotion of the proliferation and migration of resident cells [1]. The process of tissue repair consists of re-epithelization via keratinocytes, the generation of connective tissue via fibroblasts, and neo-vessel formation via endothelial cells [2,3]. Cell-free malignant pleural effusion (MPE) significantly stimulated endothelial cells with increased proliferation, migration, and angiogenesis [4,5]. The upregulation of VEGFR2 and VEGFA protein expression has been observed in MPE-cultured endothelial cells [4]. Cell-free MPE did not induce the malignant transformation of endothelial cells [6]. The importance of endothelial cells in wound healing has been well characterized to provide an optimal vascular network [7]. The current study aimed to investigate the potential of pleural fluid in cutaneous wound healing, keratinocytes, based on the positive results of cell-free MPE on the vascular endothelium
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