title: Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice.
abstract: 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.
authors.affiliation: Department of Periodontology and Oral Biology, Boston University, Boston, MA 02118, USA. gyurko@bu.edu
authors.forename: Robert
authors.initials: R
authors.lastname: Gyurko
authors.forename: Camille C
authors.initials: CC
authors.lastname: Siqueira
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Caldon
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Alpdogan
authors.initials: A
authors.lastname: Kantarci
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Van Dyke
mesh_terms: D000208:Acute Disease; D000818:Animals; D002634:Chemotaxis, Leukocyte; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism; D017354:Point Mutation; D013481:Superoxides / Q000378:metabolism; D015054:Zymosan / Q000633:toxicity
chemical_list: D016207:Cytokines; D013481:Superoxides; D015054:Zymosan