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-1α, 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.

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

“…Studies in diabetic rats have provided evidence of compromised gingival neutrophil function in vivo and in vitro (Ramamurthy et al 1979, Golub et al 1982 and studies in diabetic mice also suggest changes in gingival neutrophil function (Gyurko et al 2006, Sima et al 2010.…”

Protective Action of D-Ribose against Renal Injury Caused by Ischemia and Reperfusion in Rats with Transient Hyperglycemia

“…Further investigation is needed, however, to determine safe glucose concentrations for the preservation of renal function after I/R. Aggravation of renal injury in chronic hyperglycemia has been attributed to an elevated inflammatory state that increases oxidative stress (Gyurko et al 2006). It has been suggested that the inflammatory response in I/R-induced organ damage is injurious because I/R enhances local expression of proinflammatory cytokines, chemokines such as IL-8 (CINC-1 in rat) and adhesion molecules, and because activated neutrophils have been observed (Vedder et al 1990;Winn et al 1997).…”

“…However, the role of hyperglycemia in inducing renal dysfunction is not yet fully understood. One of the mechanisms underlying heightened renal injury seems to be an increase in inflammatory responses as seen in the kidneys of hyperglycemic animals (Gyurko et al 2006). Although the contribution of neutrophils to renal ischemia/reperfusion (I/R)-induced injury varies with the model used, many studies have suggested that neutrophil recruitment to the site of injury is a central event in the pathogenesis of renal I/R injury (Harlan 1985;Watanabe et al 1992;De Greef et al 1998).…”

VEGF Expression in Diabetic Rats Promotes Alveolar Bone Resorption by <i>Porphyromonas gingivalis</i> LPS

“…Hyperglycemia causes formation and accumulation of irreversible advanced glycation end products (AGEs) in the body 31) and induces expression of their primary receptor RAGE 32) . Interactions between the AGEs and RAGE result in the dysfunction of immune cells 6,7) and functional alterations of various cells 8,9) , causing cytokine imbalance associated with inflammatory cytokine increases 10,11) . Furthermore, hyperglycemia shifts the balance of the RANKL/OPG interaction in the direction of tissue destruction through AGEs/RAGE interaction 33,34) .…”

“…Thus far, numerous mechanisms have been reported to underlie exacerbation of periodontitis caused by diabetes mellitus. Among them, the main mechanisms involve immune dysfunction 6,7 ) , cellular stress 8,9 ) , and cytokine imbalance 10,11) caused by hyperglycemia, which enhances tissue destruction of periodontitis and impairs tissue repair. The mechanism of exacerbation of alveolar bone resorption due to cytokine imbalance is initiated when hyperglycemia increases the level of inflammatory cytokines, such as TNF- 10) , IL-1 11) , and IL-6 11) .…”