Department of Surgery, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Surg Res. 2011 May 15;167(2):336-42. doi: 10.1016/j.jss.2009.09.012. Epub 2009 Oct 23.
The interaction between neuropeptides and cytokines and its role in cutaneous wound healing is becoming evident. The goal of the present study is to investigate the impact of diabetes on peripheral cytokine and neuropeptide expression and its role in diabetic wound healing. To achieve this goal, the effect of diabetes on wound healing, along with the role of inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8) secreted in the wound microenvironment, and neuropeptides such as substance P (SP) and neuropeptide Y (NPY), secreted from peripheral nerves is monitored in non-diabetic and diabetic rabbits. Rabbits in the diabetic group received alloxan monohydrate (100mg/kg i.v.). Ten days after diabetic induction, four full thickness circular wounds were created in both ears using a 6mm punch biopsy. Wound healing was monitored over 10 d and gene expression of cytokines and neuropeptides was assessed in the wounds. Compared with the non-diabetic rabbits, wounds of diabetic rabbits heal significantly slower. Diabetic rabbits show significantly increased baseline gene expression of IL-6 and IL-8, their receptors, CXCR1, CXCR2, GP-130, and a decrease of prepro tachykinin-A (PP-TA), the precursor of SP, whereas the expression of prepro-NPY (PP-NPY), the precursor of NPY is not different. Similarly, baseline protein expression of CXCR1 is higher in diabetic rabbit skin. Post-injury, the increase over baseline gene expression of IL-6, IL-8, CXCR1, CXCR2, and GP-130 is significantly less in diabetic wounds compared with non-diabetic wounds. Although there is no difference in PP-TA gene expression between non-diabetic and diabetic rabbits post-injury, the gene expression of PP-NPY is reduced in diabetic rabbits. In conclusion, diabetes causes dysregulation in the neuropeptide expression in the skin along with a suppressed focused inflammatory response to injury. This suggests that the chronic inflammation in the skin of diabetic rabbits inhibits the acute inflammation much needed for wound healing.
神经肽和细胞因子的相互作用及其在皮肤伤口愈合中的作用正变得越来越明显。本研究的目的是探讨糖尿病对外周细胞因子和神经肽表达的影响及其在糖尿病伤口愈合中的作用。为了实现这一目标，我们监测了糖尿病对伤口愈合的影响，以及白细胞介素 6（IL-6）和白细胞介素 8（IL-8）等炎症细胞因子在伤口微环境中的分泌，以及来自周围神经的 P 物质（SP）和神经肽 Y（NPY）等神经肽的作用在非糖尿病和糖尿病兔子中。糖尿病组的兔子接受了单水合阿脲（100mg/kg 静脉注射）。糖尿病诱导 10 天后，用 6mm 打孔活检器在双耳上造成 4 个全层圆形伤口。在 10d 内监测伤口愈合情况，并评估伤口中细胞因子和神经肽的基因表达。与非糖尿病兔子相比，糖尿病兔子的伤口愈合明显较慢。糖尿病兔子的 IL-6 和 IL-8 及其受体 CXCR1、CXCR2、GP-130 的基础基因表达显著增加，前速激肽原 A（PP-TA），即 SP 的前体减少，而 NPY 的前体前体-NPY（PP-NPY）的表达无差异。同样，糖尿病兔皮肤中 CXCR1 的基础蛋白表达也较高。损伤后，与非糖尿病伤口相比，糖尿病伤口中 IL-6、IL-8、CXCR1、CXCR2 和 GP-130 的基础基因表达增加明显减少。尽管损伤后非糖尿病和糖尿病兔子的 PP-TA 基因表达无差异，但糖尿病兔子的 PP-NPY 基因表达减少。总之，糖尿病导致皮肤中神经肽表达失调，同时对损伤的集中炎症反应受到抑制。这表明糖尿病兔子皮肤中的慢性炎症抑制了伤口愈合所需的急性炎症。
