RAISED NEUTROPHIL PHOSPHOLIPASE A(2) ACTIVITY AND DEFECTIVE PRIMING OF NADPH OXIDASE AND PHOSPHOLIPASE A(2) IN SICKLE-CELL DISEASE

Intermittent painful crises due to vasoocclusion are the major clinica l manifestation of sickle cell disease (SCD), but subclinical episodes may also occur. There is sparse evidence for the involvement of neutr ophils in the pathophysiology of SCD, but production of cytokines by t he damaged endothelium might influence neutrophil function and modulat e responses to subsequent cytokine exposure. In addition, the activati on of neutrophils in the microcirculation could itself exacerbate vaso occlusion. To test whether neutrophil inflammatory responses were alte red in SCD, neutrophil phospholipase A(2) and NADPH oxidase activity i n response to in vitro priming by granulocyte-macrophage colony-stimul ating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were measured both during and between painful crises. Resting levels of ne utrophil phospholipase A(2) activity in steady-state SCD (4.0% +/- 0.5 % of total cell radioactivity) were raised relative to control values (2.0% +/- 0.2%, n = 10, P=.008). There was no defect of agonist-stimul ated phospholipase A(2) or NADPH oxidase activity in steady-state SCD: however, the ability of phospholipase A(2) to respond to priming with GM-CSF was attenuated to 63% +/- 17% of control values (n = 10, P=.04 ). Similarly, neutrophil NADPH oxidase activity after priming with GM- CSF and TNF-alpha was, respectively, 65% +/- 11% (n = 7, P=.03) and 57 % +/- 7% of control (n = 10, P=.007) in steady-state disease, and was further reduced during painful vasoocclusive crises to 34% +/- 9% and 25% +/- 3% of control for GM-CSF and TNF-alpha, respectively. These da ta were not explained by poor splenic function or any racial factor, a s normal cytokine responses were seen in splenectomized patients in re mission from Hodgkin's disease and in healthy Afro-Caribbean subjects. Abnormal neutrophil cytokine priming responses were not observed in e ither patients with rheumatoid arthritis or iron-deficiency anemia. Ou r findings are indicative of an ongoing inflammatory state in SCD betw een painful crises involving neutrophil activation and an abnormality of cytokine-regulated neutrophil function, which may compromise the ho st defenses against certain microorganisms. (C) 1998 by The American S ociety of Hematology.