Topical Application of a Mast Cell Stabilizer Improves Impaired Diabetic Wound Healing

伤口愈合 炎症 肥大细胞 脱颗粒 医学 糖尿病足 下调和上调 免疫学 药理学 糖尿病 生物 内科学 内分泌学 受体 生物化学 基因
作者
Ana Tellechea,Sha Bai,Seema Dangwal,Georgios Theocharidis,Masazumi Nagai,Steffi Koerner,Jae Eun Cheong,Swati S. Bhasin,Ting‐Yu Shih,Yongjun Zheng,Wanni Zhao,Cuiping Zhang,Xiaoli Li,Konstantinos Kounas,Smaro Panagiotidou,Theoharis C. Theoharides,David Mooney,Manoj Bhasin,Lijun Sun,Aristidis Veves
出处
期刊:Journal of Investigative Dermatology [Elsevier BV]
卷期号:140 (4): 901-911.e11 被引量:58
标识
DOI:10.1016/j.jid.2019.08.449
摘要

Impaired wound healing in the diabetic foot is a major problem often leading to amputation. Mast cells have been shown to regulate wound healing in diabetes. We developed an indole-carboxamide type mast cell stabilizer, MCS-01, which proved to be an effective mast cell degranulation inhibitor in vitro and can be delivered topically for prolonged periods through controlled release by specifically designed alginate bandages. In diabetic mice, both pre- and post-wounding, topical MCS-01 application accelerated wound healing comparable to that achieved with systemic mast cell stabilization. Moreover, MCS-01 altered the macrophage phenotype, promoting classically activated polarization. Bulk transcriptome analysis from wounds treated with MCS-01 or placebo showed that MCS-01 significantly modulated the mRNA and microRNA profile of diabetic wounds, stimulated upregulation of pathways linked to acute inflammation and immune cell migration, and activated the NF-κB complex along with other master regulators of inflammation. Single-cell RNA sequencing analysis of 6,154 cells from wounded and unwounded mouse skin revealed that MCS-01 primarily altered the gene expression of mast cells, monocytes, and keratinocytes. Taken together, these findings offer insights into the process of diabetic wound healing and suggest topical mast cell stabilization as a potentially successful treatment for diabetic foot ulceration.
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