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(Circulation. 2003;108:1858.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Advanced Glycation End Products Stimulate an Enhanced Neutrophil Respiratory Burst Mediated Through the Activation of Cytosolic Phospholipase A₂ and Generation of Arachidonic Acid

Richard K.M. Wong, MA, MRCP; Andrew I. Pettit, BSc, MRCP; Paulene A. Quinn, MPhil; Sonja C. Jennings, HNC; Joan E. Davies, PhD, FRCP; Leong L. Ng, MD, FRCP

From the Division of Medicine and Therapeutics, University of Leicester, Leicester Royal Infirmary, Leicester, UK.

Correspondence to Prof L.L. Ng, Division of Medicine and Therapeutics, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK. E-mail lln1{at}le.ac.uk

Received December 17, 2002; de novo received April 8, 2003; revision received May 22, 2003; accepted June 6, 2003.

Background— Advanced glycation end products (AGEs) enhance NADPH oxidase, and hence respiratory burst activity, of stimulated neutrophils. They are thus potentially vasculopathic, especially in diabetes, uremia, and aging, in which AGEs classically accumulate. We investigated the underlying mechanisms.

Methods and Results— Neutrophils prelabeled with [³H]arachidonic acid display increased [³H]arachidonate release on exposure to AGE-albumin over exposure to albumin alone (by 151±16%, P<0.01). Arachidonic acid (AA) itself seems to mediate the AGE-augmented neutrophil respiratory burst (ascertained by chemiluminescence). Inhibitors of the cyclooxygenase pathway (indomethacin) and lipoxygenase pathway (MK-886) do not impair this AGE effect, excluding a contribution from AA metabolites. Cytosolic phospholipase A₂ (cPLA₂) controls AA generation. Its inhibition by methyl arachidonyl fluorophosphonate abrogates the AGE-enhanced activated neutrophil respiratory burst, and it is demonstrably stimulated in AGE-exposed neutrophils, as evidenced by isoform gel-shift and an increasingly membrane-translocated state in Western blots of neutrophil subfractions. Inhibition of other PLA₂ isoforms, secretory PLA₂ and calcium-independent PLA₂, by manoalide and haloenol-lactone suicide substrate, respectively, does not affect this effect of AGEs relative to inhibitor-treated controls. The thiol antioxidant NAC reduces activation of cPLA₂ (assessed by isoform gel-shift and membrane translocation), production of AA in AGE-albumin–exposed neutrophils (H³ release reduced to 104±17%, P=0.94 compared with albumin-exposed neutrophils), and the AGE-augmented neutrophil respiratory burst.

Conclusions— AGE augmentation of the activated neutrophil respiratory burst requires AA generation, through which neutrophil NADPH oxidase may be upregulated, enhancing reactive oxygen species output. AA is generated by cPLA₂, which may be stimulated through an AGE-activated redox-sensitive pathway.

Key Words: glycosylation end products, advanced • phospholipases • arachidonic acid • free radicals • NADPH oxidase

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