Department of Medicinal Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.
Department of Analysis and Bioanalysis of Medicines, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland.
Molecules. 2023 Jan 14;28(2):851. doi: 10.3390/molecules28020851.
The potential of recombinant human prolidase (rhPEPD) to induce wound healing in an experimental model of IL-1β-induced inflammation in human fibroblasts was studied. It was found that rhPEPD significantly increased cell proliferation and viability, as well as the expression of the epidermal growth factor receptor (EGFR) and downstream signaling proteins, such as phosphorylated PI3K, AKT, and mTOR, in the studied model. Moreover, rhPEPD upregulated the expression of the β1 integrin receptor and its downstream signaling proteins, such as p-FAK, Grb2 and p-ERK 1/2. The inhibition of EGFR signaling by gefitinib abolished rhPEPD-dependent functions in an experimental model of inflammation. Subsequent studies showed that rhPEPD augmented collagen biosynthesis in IL-1β-treated fibroblasts as well as in a wound healing model (wound closure/scratch test). Although IL-1β treatment of fibroblasts increased cell migration, rhPEPD significantly enhanced this process. This effect was accompanied by an increase in the activity of MMP-2 and MMP-9, suggesting extracellular matrix (ECM) remodeling during the inflammatory process. The data suggest that rhPEPD may play an important role in EGFR-dependent cell growth in an experimental model of inflammation in human fibroblasts, and this knowledge may be useful for further approaches to the treatment of abnormalities of wound healing and other skin diseases.
研究了重组人脯氨酰内肽酶（rhPEPD）在白细胞介素-1β诱导的人成纤维细胞炎症模型中诱导伤口愈合的潜力。结果发现，rhPEPD 显著增加了细胞增殖和活力，以及表皮生长因子受体（EGFR）及其下游信号蛋白的表达，如磷酸化 PI3K、AKT 和 mTOR。此外，rhPEPD 上调了β1 整合素受体及其下游信号蛋白，如 p-FAK、Grb2 和 p-ERK1/2 的表达。用吉非替尼抑制 EGFR 信号通路可消除 rhPEPD 在炎症模型中的依赖性作用。随后的研究表明，rhPEPD 增强了 IL-1β处理的成纤维细胞以及伤口愈合模型（伤口闭合/划痕试验）中的胶原生物合成。尽管 IL-1β 处理成纤维细胞增加了细胞迁移，但 rhPEPD 显著增强了这一过程。这种作用伴随着 MMP-2 和 MMP-9 活性的增加，表明在炎症过程中细胞外基质（ECM）重塑。数据表明，rhPEPD 可能在人成纤维细胞炎症模型中 EGFR 依赖性细胞生长中发挥重要作用，这一知识可能有助于进一步治疗伤口愈合异常和其他皮肤病。
