New England Society for Vascular Surgery

June 22, 2006

Evidence Of A Sustained Inflammatory Response In A Murine Model Of Type II Diabetes Following Unilateral Hind-Limb Ischemia Reperfusion Injury

Marvin D Atkins, Jr.*, Hassan Albadawi, Fateh Entabi, John E. Jones, Robert S. Crawford, Michael T. Watkins
Massachusetts General Hospital, Boston, MA

Introduction: Patients with diabetes have a high incidence of peripheral vascular disease and limb loss despite successful vascular reconstruction. These experiments were designed to evaluate the temporal inflammatory response of acute limb ischemia reperfusion injury in a murine model of type 2 diabetes.
Methods: Db (Leptin receptor mutant - hyperinsulinemic, hyperlipidemic, obese mice) and wild type (Wt) mice were both subjected to 1.5 hours of unilateral hind-limb ischemia followed by either 1 or 7 days of reperfusion (DR). After reperfusion, murine limbs were assayed for tissue levels of the pro-inflammatory cytokines MIP-2, MCP-1 (Macrophage Inflammatory Protein-2, Monocyte Chemoattractant Protein-1, inflammatory cell chemoattractants), and Myeloperoxidase levels (MPO, marker of inflammatory cell infiltration) using ELISA.
Results (see Table):


	MPO ng/mg	MCP-1 pg/mg	MIP-2 pg/mg
Wt (1DR) n=5	72.2±10	726.7±30	42.1±9
Wt (7DR) n=5	23.1±3	124.9±18	3.6±1

Db (1DR) n=5	180.6±41	530.6±131	103.4±39
Db (7DR) n=5	161.9±51	341.9±44	52.1±11

After 7DR, levels of MPO, MCP-1, and MIP-2 were markedly increased in the Db as compared to Wt mice (p<0.002). Between 1DR and 7DR, MPO, MCP-1 and MIP-2 levels significantly decreased in Wt mice (p<0.03), however they remained elevated in the Db mice.
Conclusion: During post ischemic reperfusion, Db mice exhibit a persistent elevation in tissue levels of pro-inflammatory cytokines and markers of inflammatory cell activation. The sustained inflammatory response detected exclusively in Db mice may provide clues regarding the etiology of ongoing tissue injury and limb loss in diabetic patients.

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