糖尿病小鼠模型中创伤愈合受损是由 TNF-α 失调介导的，并与叉头框 O1（FOXO1）的激活增强有关。
Impaired wound healing in mouse models of diabetes is mediated by TNF-alpha dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1).
机构信息
Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA, USA.
出版信息
Diabetologia. 2010 Feb;53(2):378-88. doi: 10.1007/s00125-009-1529-y. Epub 2009 Nov 10.
AIMS/HYPOTHESIS: The role of TNF-alpha in impaired wound healing in diabetes was examined by focusing on fibroblasts.
METHODS
Small excisional wounds were created in the db/db mice model of type 2 diabetes and normoglycaemic littermates, and in a streptozotocin-induced type 1 diabetes mouse model and control mice. Fibroblast apoptosis was measured by the TUNEL assay, proliferation by detection of proliferating cell nuclear antigen, and forkhead box O1 (FOXO1) activity by DNA binding and nuclear translocation. TNF-alpha was specifically inhibited by pegsunercept.
RESULTS
Diabetic wounds had increased TNF-alpha, fibroblast apoptosis, caspase-3/7 activity and activation of the pro-apoptotic transcription factor FOXO1, and decreased proliferating cell nuclear antigen positive fibroblasts (p < 0.05). TNF-alpha inhibition improved healing in the diabetic mice and increased fibroblast density. This may be explained by a decrease in fibroblast apoptosis and increased proliferation when TNF-alpha was blocked (p < 0.05). Although decreased fibroblast proliferation and enhanced FOXO1 activity were investigated in type 2 diabetes, they may also be implicated in type 1 diabetes. In vitro, TNF-alpha enhanced mRNA levels of gene sets related to apoptosis and Akt and p53 but not mitochondrial or cell-cycle pathways. FOXO1 small interfering RNA reduced gene sets that regulate apoptosis, Akt, mitochondrial and cell-cycle pathways. TNF-alpha also increased genes involved in inflammation, cytokine, Toll-like receptor and nuclear factor-kB pathways, which were significantly reduced by FOXO1 knockdown.
CONCLUSIONS/INTERPRETATION: These studies indicate that TNF-alpha dysregulation in diabetic wounds impairs healing, which may involve enhanced fibroblast apoptosis and decreased proliferation. In vitro, TNF-alpha induced gene sets through FOXO1 that regulate a number of pathways that could influence inflammation and apoptosis.
目的/假设：本研究通过聚焦于成纤维细胞，探讨 TNF-α 在糖尿病受损伤口愈合中的作用。
方法
在 2 型糖尿病 db/db 小鼠模型及其血糖正常的同窝仔鼠、链脲佐菌素诱导的 1 型糖尿病小鼠模型及其对照鼠中，制造小的切除性创面。通过 TUNEL 检测，增殖细胞核抗原检测法检测增殖，DNA 结合和核易位检测叉头框 O1（FOXO1）活性，测量成纤维细胞凋亡、增殖。通过 pegsunercept 特异性抑制 TNF-α。
结果
糖尿病创面 TNF-α 增加、成纤维细胞凋亡、半胱天冬酶-3/7 活性和促凋亡转录因子 FOXO1 激活，增殖细胞核抗原阳性成纤维细胞减少（p < 0.05）。在糖尿病小鼠中，TNF-α 抑制改善了愈合，增加了成纤维细胞密度。当阻断 TNF-α 时，这可能归因于成纤维细胞凋亡减少和增殖增加（p < 0.05）。尽管在 2 型糖尿病中研究了成纤维细胞增殖减少和 FOXO1 活性增强，但它们也可能与 1 型糖尿病有关。在体外，TNF-α 增强了与凋亡和 Akt、p53 相关的基因集的 mRNA 水平，但不影响线粒体或细胞周期途径。FOXO1 小干扰 RNA 减少了调节凋亡、Akt、线粒体和细胞周期途径的基因集。TNF-α 还增加了与炎症、细胞因子、Toll 样受体和核因子-kB 途径相关的基因，这些基因在 FOXO1 敲低时显著减少。
结论/解释：这些研究表明，糖尿病创面中 TNF-α 的失调会损害愈合，这可能涉及增强的成纤维细胞凋亡和减少的增殖。在体外，TNF-α 通过 FOXO1 诱导调节许多可能影响炎症和凋亡的途径的基因集。
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