Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.
Research Center for Experimental Modeling of Human Disease, Kanazawa University, Ishikawa, Japan.
PLoS One. 2022 Mar 10;17(3):e0264572. doi: 10.1371/journal.pone.0264572. eCollection 2022.
Female sex hormones are beneficial effects for wound healing. However, till date, whether topical estrogen application can promote cutaneous wound healing in diabetes remains unclear. Therefore, the present study aimed to validate the effect of topical estrogen application on cutaneous wound healing in a type 2 diabetes db/db mice model. In total, 22 db/db female mice with type 2 diabetes and eight C57BL/6J female mice were subjected to two full-thickness wound injuries. The mice were divided into the db/db, db/db + estrogen, db/db + vehicle, and wild type (WT) groups. Wound healing was assessed until day 14. The db/db group had a significantly high wound area ratio (wound area/initial wound area) on days 3-14 and a significantly low re-epithelialization ratio on days 7 and 14. Moreover, their angiogenesis ratio was significantly low on day 7 and high on day 14. In contrast, compared with the db/db group, the db/db + estrogen group had a significantly lower wound area ratio on days 1-14 and angiogenesis ratio on day 14, thereby indicating early withdrawal of new blood vessels, as well as a significantly higher re-epithelialization ratio on days 7 and 14 and Ym1+ M2 macrophage/macrophage ratio on day 7. Moreover, microarray analysis showed that the top 10 upregulated or downregulated genes in the db/db group were reversed by estrogen treatment, particularly on day 14, in comparison with the WT group. Thus, topical estrogen application reduced the wound area, promoted re-epithelialization and angiogenesis, and increased the number of M2 macrophages in mice with type 2 diabetes. Furthermore, it improved the differential regulation of genes in db/db mice. Therefore, such treatment can enhance cutaneous wound healing in female mice with type 2 diabetes.
女性性激素对伤口愈合有有益作用。然而，迄今为止，局部应用雌激素是否能促进糖尿病患者的皮肤伤口愈合仍不清楚。因此，本研究旨在验证局部应用雌激素对 2 型糖尿病 db/db 小鼠模型皮肤伤口愈合的影响。总共对 22 只患有 2 型糖尿病的 db/db 雌性小鼠和 8 只 C57BL/6J 雌性小鼠进行了两次全层伤口损伤。将小鼠分为 db/db、db/db+雌激素、db/db+载体和野生型（WT）组。评估伤口愈合情况，直至第 14 天。db/db 组在第 3-14 天的伤口面积比（伤口面积/初始伤口面积）显著较高，在第 7 和 14 天的再上皮化率显著较低。此外，其血管生成比例在第 7 天显著较低，在第 14 天显著较高。相比之下，与 db/db 组相比，db/db+雌激素组在第 1-14 天的伤口面积比和第 14 天的血管生成比显著较低，表明新血管早期退缩，以及第 7 和 14 天的再上皮化率和第 7 天的 Ym1+M2 巨噬细胞/巨噬细胞比显著较高。此外，微阵列分析显示，db/db 组中前 10 个上调或下调的基因在雌激素治疗后发生逆转，特别是与 WT 组相比，在第 14 天。因此，局部应用雌激素可减少糖尿病小鼠的伤口面积，促进再上皮化和血管生成，并增加 2 型糖尿病小鼠 M2 巨噬细胞的数量。此外，它改善了 db/db 小鼠中基因的差异调控。因此，这种治疗可以增强 2 型糖尿病女性小鼠的皮肤伤口愈合。
