Al-Mashat Hesham A, Kandru Suneel, Liu Rongkun, Behl Yugal, Desta Tesfahun, Graves Dana T
Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA.
Diabetes. 2006 Feb;55(2):487-95. doi: 10.2337/diabetes.55.02.06.db05-1201.
We previously reported that after a bacteria-induced wound in the scalp, type 2 diabetic (db/db) mice had higher levels of apoptosis of fibroblasts and bone-lining cells that are critical for healing compared with normoglycemic controls. To investigate mechanisms by which this might occur, RNA profiling and caspase activity was measured after inoculation of Porphyromonas gingivalis. Diabetes caused a more than twofold induction of 71 genes that directly or indirectly regulate apoptosis and significantly enhanced caspase-8, -9, and -3 activity. The functional significance of diabetes-induced apoptosis was studied by treating diabetic mice with a pancaspase inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone). Inhibiting apoptosis significantly improved several parameters of healing, including fibroblast density, enhanced mRNA levels of collagen I and III, and increased matrix formation. Improvements were also noted in bone, with an increase in the number of bone-lining cells and new bone formation. Thus, diabetes-enhanced apoptosis represents an important mechanism through which healing is impaired, and this can be explained, in part, by diabetes-increased expression of proapoptotic genes and caspase activity.
我们之前报道过，在头皮细菌诱导伤口后，与血糖正常的对照组相比，2型糖尿病（db/db）小鼠中对愈合至关重要的成纤维细胞和骨衬细胞的凋亡水平更高。为了研究这种情况可能发生的机制，在接种牙龈卟啉单胞菌后测量了RNA谱和半胱天冬酶活性。糖尿病导致71个直接或间接调节凋亡的基因诱导增加两倍以上，并显著增强了半胱天冬酶-8、-9和-3的活性。通过用泛半胱天冬酶抑制剂z-VAD-fmk（N-苄氧羰基-Val-Ala-Asp-氟甲基酮）治疗糖尿病小鼠，研究了糖尿病诱导凋亡的功能意义。抑制凋亡显著改善了几个愈合参数，包括成纤维细胞密度、I型和III型胶原蛋白mRNA水平的提高以及基质形成的增加。在骨骼方面也观察到改善，骨衬细胞数量增加和新骨形成。因此，糖尿病增强的凋亡是愈合受损的一个重要机制，这部分可以通过糖尿病促凋亡基因表达增加和半胱天冬酶活性来解释。
