Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice
Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice
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DOI：
10.4049/jimmunol.177.10.7250
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Van Dyke, Thomas E.
中科院分区：
文献类型：
--
作者：
Gyurko, Robert;Siqueira, Camille C.;Van Dyke, Thomas E.
在慢性高血糖的新模型秋田小鼠中研究了多形核中性粒细胞（PMN）在介导糖尿病牙周组织损伤中的作用。在野生型（WT）和秋田小鼠中诱导急性腹膜炎症导致秋田小鼠中IL-6反应增强（比WT值增加2.9倍）和趋化因子反应显著增加（KC，2.6倍; MCP-1，2.6倍; MIP-1 α，比WT值增加4.4倍）。与WT PMN相比，在Boyden室中测量的分离的秋田PMN对fMLP和WKYMVm的趋化性显著降低。与此相反，超氧化物释放显着增加，在秋田PMN细胞色素c还原测定。骨髓来源的秋田中性粒细胞显示p47（phox）的部分易位到细胞膜没有外部刺激，表明过早组装的超氧化物产生NADPH氧化酶在高血糖症。体内研究显示，与WT相比，秋田小鼠中结扎诱导的牙周骨丢失显著更大。此外，牙龈血管的活体显微镜显示，白细胞滚动和附着在血管内皮细胞增强秋田小鼠牙周血管。这些结果表明，慢性高血糖倾向于夸大的炎症反应，并启动白细胞边缘化和超氧化物的生产，但不为轮回。因此，高血糖症中的白细胞缺陷可能通过损害对牙周病原体的先天免疫应答以及通过增加牙龈微血管中的自由基负荷而导致牙周组织损伤。
The role of polymorphonuclear neutrophils (PMN) in mediating diabetic tissue damage to the periodontium was investigated in a novel model of chronic hyperglycemia, the Akita mouse. Induction of acute peritoneal inflammation in wild-type (WT) and Akita mice resulted in exaggerated IL-6 response in Akita mice (2.9-fold increase over WT values) and a markedly increased chemokine response (KC, 2.6-fold; MCP-1, 2.6-fold; and MIP-1 alpha, 4.4-fold increase over WT values). Chemotaxis to both fMLP and WKYMVm was significantly reduced in isolated Akita PMN compared with WT PMN as measured in a Boyden chamber. Superoxide release in contrast was significantly increased in Akita PMN as measured with cytochrome c reduction. Bone marrow-derived Akita PMN showed partial translocation of p47(phox) to the cell membrane without external stimulation, suggesting premature assembly of the superoxide-producing NADPH oxidase in hyperglycemia. In vivo studies revealed that ligature-induced periodontal bone loss is significantly greater in Akita mice compared with WT. Moreover, intravital microscopy of gingival vessels showed that leukocyte rolling and attachment to the vascular endothelium is enhanced in periodontal vessels of Akita mice. These results indicate that chronic hyperglycemia predisposes to exaggerated inflammatory response and primes leukocytes for marginalization and superoxide production but not for transmigration. Thus, leukocyte defects in hyperglycemia may contribute to periodontal tissue damage by impairing the innate immune response to periodontal pathogens as well as by increasing free radical load in the gingival microvasculature.