中性粒细胞对糖尿病皮肤组织的隐性损害及其机制

Recently our research team found that pathological changes of diabetic skin, including skin thinning, collagen degeneration, a large number of advanced glycation end products (AGEs) local accumulation and diffuse infiltration of inflammatory cells, are different to the secondary damage of vascular and nerve. This phenomenon is called potential damage skin tissue. The diffuse infiltration of neutrophils (PMN) is an important characteristic of the damage of skin. Then, what is the relationship between the local accumulations of AGEs and diffuse infiltration of PMN. What is the mechanism of the infiltration of PMN in diabetic skin tissue？ PMN can release Inflammatory factors and proteases, its new functions are constantly being discovered, then, the accumulation and infiltration of PMN, will produce what kind of damage to the diabetic skin? Therefore, this study intends to elucidate the mechanism of PMN infiltration and the damage effect of PMN through the animal model and in vitro cytological and molecular biology experiments. This study will provide a theoretical basis for understanding potential damage of skin tissue of diabetic.

我们课题组近期的研究发现，糖尿病皮肤组织在未形成溃疡前就已发生了包括皮肤变薄、胶原变性、大量糖基化终末产物（AGEs）局部蓄积和弥漫性炎性细胞浸润等病理性改变，有别于血管神经病变导致继发性损害的传统认识，被称作为皮肤组织隐性损害。其中弥漫性中性粒细胞（PMN）浸润是皮肤隐性损害的重要特征。那么，局部蓄积具有强趋化性的AGEs与PMN的弥漫性浸润是什么关系呢？其发生机制是什么？PMN具有释放炎症因子及各种蛋白酶释的活性，其新的功能也在不断被发现，那么，PMN的大量蓄积、浸润对糖尿病皮肤会产生何种损害呢？值得深入研究。因此，本研究拟通过动物模型并结合体外细胞学实验两部分来阐明糖尿病皮肤组织中PMN弥漫性浸润的发生机制及其对皮肤组织的损害作用，为阐明糖尿病皮肤隐性损害现象提供理论依据。

糖尿病创伤发生前，大鼠表皮局部组织变薄，凹陷，可见局部感染，炎症细胞浸润，胶原淡染、失去柔性，局部出现了玻璃样变及水样变性，神经组织挤压变性失去圆润的特性，脂肪组织出现液化，大量毛细血管表现僵硬。在炎症方面，免疫防御相关的因子IL-1β及TNFa的表达降低，创面组织中的NETs释放大量增加。但是，细胞学实验显示，AGEs（晚期糖基化终末产物）可以抑制中性粒细胞释放NETS、IL-1β及TNFa，促进中性粒细胞的迁移，增加中性粒细胞的凋亡率，且与糖尿病动物模型表现一致，抑制AGEs表达后可以逆转这一结果。实验证明：在糖尿病创面形成前，皮肤组织中沉积的AGEs诱导中性粒细胞浸入到皮肤组织中，并被中性粒细胞吞噬，吞噬AGEs后的中性粒细胞释放NET、IL-1β及TNFa功能降低，使皮肤组织的防御功能减弱，创伤发生后，中性粒细胞释放NETs功能异常增强，导致创面呈现过度炎症状态，阻碍创面愈合。