Li Lingfei, Zhang Junhui, Zhang Qiong, Zhang Dongxia, Xiang Fei, Jia Jiezhi, Wei Ping, Zhang Jiaping, Hu Jiongyu, Huang Yuesheng
Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Front Physiol. 2019 Jan 28;10:24. doi: 10.3389/fphys.2019.00024. eCollection 2019.
Wound healing is delayed frequently in patients with diabetes. Proper keratinocyte migration is an essential step during re-epithelialization. Impaired keratinocyte migration is a critical underlying factor responsible for the deficiency of diabetic wound healing, which is mainly attributed to the hyperglycemic state. However, the underlying mechanisms remain largely unknown. Previously, we demonstrated a marked activation of p38/mitogen-activated protein kinase (MAPK) pathway in the regenerated migrating epidermis, which in turn promoted keratinocyte migration. In the present study, we find that p38/MAPK pathway is downregulated and accompanied by inactivation of autophagy under high glucose (HG) environment. In addition, we demonstrate that inactivation of p38/MAPK and autophagy result in the inhibition of keratinocyte migration under HG environment, and the activating p38/MAPK by MKK6(Glu) overexpression rescues cell migration through an autophagy-dependent way. Moreover, diabetic wound epidermis shows a significant inhibition of p38/MAPK and autophagy. Targeting these dysfunctions may provide novel therapeutic approaches.
糖尿病患者的伤口愈合常常延迟。角质形成细胞的正常迁移是再上皮化过程中的一个关键步骤。角质形成细胞迁移受损是导致糖尿病伤口愈合不足的一个关键潜在因素，这主要归因于高血糖状态。然而，其潜在机制在很大程度上仍不清楚。此前，我们证明了再生迁移表皮中p38/丝裂原活化蛋白激酶（MAPK）通路的显著激活，这反过来又促进了角质形成细胞的迁移。在本研究中，我们发现p38/MAPK通路在高糖（HG）环境下被下调，并伴有自噬失活。此外，我们证明p38/MAPK和自噬的失活导致HG环境下角质形成细胞迁移受到抑制，通过MKK6（Glu）过表达激活p38/MAPK可通过自噬依赖性方式挽救细胞迁移。此外，糖尿病伤口表皮显示出p38/MAPK和自噬的显著抑制。针对这些功能障碍可能提供新的治疗方法。
