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The Journal of Immunology, 2006, 177: 7250-7256.
Copyright © 2006 by The American Association of Immunologists, Inc.

Chronic Hyperglycemia Predisposes to Exaggerated Inflammatory Response and Leukocyte Dysfunction in Akita Mice1

Robert Gyurko2, Camille C. Siqueira, Nathaniel Caldon, Li Gao, Alpdogan Kantarci and Thomas E. Van Dyke

Department of Periodontology and Oral Biology, Boston University, Boston, MA 02118

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 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by U.S. Public Health Service Grants DE14568, DE16933, and DE15566.

2 Address correspondence and reprint requests to Dr. Robert Gyurko, 100 East Newton Street, Suite 107, Boston, MA 02118. E-mail address: gyurko{at}bu.edu

3 Abbreviations used in this paper: AGE, advanced end glycation; PMN, polymorphonuclear neutrophil; WT, wild type; BM, bone marrow; CEJ-ABC, cementoenamel junction and alveolar bone crest distance.




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