Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with healthy individuals. Isolated PMNs bound free MPO by a CD11b͞CD18 integrin-dependent mechanism. PMNs exposed to MPO were characterized by increased tyrosine phosphorylation and p38 mitogen-activated protein kinase activation. Also, nuclear translocation of NF B in PMN was enhanced after incubation with MPO, as was surface expression of CD11b. Binding of PMN to MPO-coated fibronectin surfaces amplified PMN degranulation, as evidenced by increased release of MPO and elastase. MPO also augmented PMN-dependent superoxide (O 2 •؊ ) production, which was prevented by anti-CD11b antibodies, but not MPO inhibitors. Collectively, these results reveal that binding of MPO to CD11b͞CD18 integrins stimulates PMN signaling pathways to induce PMN activation in a mechanism independent of MPO catalytic activity. These cytokine-like properties of MPO thus represent an additional dimension of the proinflammatory actions of MPO in vascular disease.atherosclerosis ͉ cytokine ͉ endothelium ͉ leukocyte ͉ nitric oxide

Background-Oxidative stress is involved in the pathophysiology of atherosclerosis, diabetes mellitus, hypertension, obesity, and cigarette smoking, all of these being risk factors for coronary heart disease (CHD). We tested the hypothesis that risk factors of CHD are associated with abundant systemic oxidative stress. Methods and Results-We conducted a case-control study with 93 CHD patients and 93 control subjects frequencymatched by age and sex. Urinary excretion of the F 2 -isoprostane 8-iso-prostaglandin (PG) F 2␣ and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF 2␣ , were measured by gas chromatography-tandem mass spectrometry. Body mass index, systolic blood pressure, and C-reactive protein were elevated in CHD patients (PϽ0.01). Urinary 8-iso-PGF 2␣ and 2,3-dinor-5,6-dihydro-8-iso-PGF 2␣ also differed, from 77 (interquartile range, 61-101) to 139 (93-231) pmol/mmol creatinine and from 120 (91-151) to 193 (140 -275) pmol/mmol in control subjects and case subjects, respectively (PϽ0.001). 8-iso-PGF 2␣ and its metabolite were highly correlated (Spearman's ϭ0.664, PϽ0.001). HDL cholesterol was diminished in CHD patients (PϽ0.001). All of these characteristics predicted CHD in univariate analysis. In a multivariate model, the odds ratios were increased only for 8-iso-PGF 2␣ (Ն131 pmol/mmol, PϽ0.001) and C-reactive protein (Ͼ3 mg/L, PϽ0.01), ie, by 30.8 (95% CI, 7.7-124) and 7.2 (1.9 -27.6), respectively. 8-iso-PGF 2␣ was found to be a novel marker in addition to known risk factors of CHD, ie, diabetes mellitus, hypercholesterolemia, hypertension, and smoking. Urinary excretion of 8-iso-PGF 2␣ correlated with the number of risk factors for all subjects (PϽ0.001 for trend). Conclusions-8-iso-PGF