(Circulation. 1996;93:161-167.)
© 1996 American Heart Association, Inc.
Articles |
Diabetes Exacerbates Inflammatory Responses to Ischemia-Reperfusion
From the Department of Physiology, Louisiana State University Medical Center, Shreveport; the Discovery Research, UpJohn Laboratories, Kalamazoo, Mich (D.C.A.); and the Department of Bioregulation, Biomedical Research Center, Osaka University Medical School, Japan (M.M.).
Correspondence to D. Neil Granger, PhD, Department of Physiology, LSU Medical Center, 1501 Kings Hwy, PO Box 33932, Shreveport, LA 71130-3932. E-mail dgrang@lsumc.edu.
Background Diabetes is associated with an increased incidence of ischemic organ damage. The objectives of present study were to compare the leukocyte–endothelial cell adhesive interactions and albumin leakage response of mesenteric venules to ischemia-reperfusion between control rats, rats with streptozotocin-induced diabetes, and rats with hyperglycemia induced by glucose infusion and to define the molecular determinants of the leukocyte accumulation elicited by ischemia-reperfusion in diabetic rats.
Methods and Results Under baseline conditions, lower venular shear rates and an increased number of rolling leukocytes were noted in diabetic rats, whereas the number of adherent and emigrated leukocytes did not differ from that in control rats. Spontaneous albumin leakage from mesenteric venules was markedly increased in diabetic rats but not in hyperglycemic nondiabetic rats. Ischemia-reperfusion elicited significantly larger increases in leukocyte adhesion and emigration and albumin leakage in diabetic rats. Acute elevation of glucose levels did not modify the microvascular responses to ischemia-reperfusion compared with control rats. Antibodies directed against CD11/CD18, intercellular adhesion molecule–1 (ICAM-1), or P-selectin but not L-selectin significantly decreased the number of adherent and emigrated leukocytes after ischemia-reperfusion in diabetic rats. However, none of the antibodies significantly attenuated the increased albumin leakage response to ischemia-reperfusion in diabetic rats.
Conclusions Thes results indicate that diabetes mellitus is associated with exaggerated leukocyte–endothelial cell adhesion and albumin leakage responses to ischemia-reperfusion. The enhanced leukocyte accumulation in response to ischemia-reperfusion is mediated by CD11/CD18–ICAM-1 interactions (firm adhesion) and P-selectin (rolling). The exaggerated albumin leakage response to ischemia-reperfusion in diabetics is not mediated by the recruited inflammatory cells.
Key Words: ischemia • reperfusion • leukocytes • microcirculation • risk factors
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