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-1alpha, 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 p47phox 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.