Augmentation of the neutrophil respiratory burst through the action of advanced glycation end products: a potential contributor to vascular oxidant stress.
An accelerated accumulation of advanced glycation end products (AGEs) occurs in diabetes secondary to the increased glycemic burden. In this study, we investigated the contribution of AGEs to intravascular oxidant stress by examining their action on the neutrophil burst of reactive oxygen species (ROS); this may be a significant donor to the overall vascular redox status and to vasculopathy. AGEs exerted a dose-dependent enhancement on the neutrophil respiratory burst in response to a secondary mechanical stimulus (up to 265 +/- 42%, P = 0.022) or chemical stimulation with formyl-methylleucylphenylalanine 100 nmol/l (up to 218 +/- 19%, P < 0.001), although they possessed no ability to augment the neutrophil respiratory burst alone. This phenomenon was both immediate and reversible and depended on the simultaneous presence of AGEs with the additional stimulus. It appeared to work through an upregulation of the neutrophil NADPH oxidase, the enzyme responsible for ROS generation, as seen by a diphenyleneiodonium-dependent suppression of basal and augmented ROS output. Moreover, this action of AGEs was found to be complementary to that of neutrophil priming agents, also known to upregulate neutrophil ROS production, implying the presence of distinct intracellular transduction pathways mediating the effect of these two classes of agents.
Division of Medicine and Therapeutics, University of Leicester, Leicester, U.K. lln1@le.ac.uk
Richard K M
RK
Wong
Andrew I
AI
Pettit
Joan E
JE
Davies
Leong L
LL
Ng
D000328:Adult; D001808:Blood Vessels / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress; D010812:Physical Stimulation; D010972:Platelet Activating Factor / Q000494:pharmacology; D016897:Respiratory Burst / Q000502:physiology*; D012709:Serum Albumin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017127:Glycation End Products, Advanced; D010972:Platelet Activating Factor; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine