Abstract

The acute chest syndrome (ACS) is a form of acute lung injury (ALI) unique to sickle cell disease (SCD), and for children >10 years of age represents the major cause of morbidity and mortality. ALI is thought to be neutrophil (PMN)-mediated; however, the pathogenesis of ACS is not known but is linked to an increase of secretory phospholipase A2-IIA (sPLA2) activity within 24 hours of its development (

Styles,
Blood
87
:
2573
,
1996
). We hypothesize that sPLA2 cleavage of membrane lipids generates biologically active lipophilic compounds that prime PMNs, which provokes ACS in patients with SCD, resulting in increased lipid priming activity during ACS. After obtaining informed consent, heparinized whole blood was drawn from children with SCD when well, at their annual comprehensive visit, and serially when admitted to the hospital, upon admission and every other day until discharge. Plasma was isolated, and the plasma lipids extracted. In selected patients the plasma was treated with buffer or sPLA2 for 1 hour at 37°C prior to lipid extraction. Lipids were assayed for their ability to prime fMLP-activation of the PMN oxidase as measured by the maximal rate of O2 production by the SOD-inhibitable reduction of cytochrome c at 550 nm. The data (mean ± SEM of fold increase over fMLP-treated controls of the lipid priming activity at baseline and over hospitalization) consists of three groups: patients with SCD, patients with SCD treated with daily hydroxyurea (HU), or patients with SCD treated with monthly, red cell exchanges (EX). At baseline, there was slightly more lipid priming activity in untreated SCD patients versus either HU- or EX-treated patients, which was not statistically different (Table). The lipid activity did not increase with vaso-occlusive crisis (VOC) but significantly increased in the one patient with ACS. Moreover, sPLA2 treatment of the plasma obtained 12 hours prior to developing ACS, while this patient was in VOC, demonstrated an increase in lipid priming activity versus the patient’s prior samples (0.96- to 1.73-fold control with sPLA2). The lipids from healthy African-American patients, did not exhibit increased activity vs controls (data not shown). We conclude that both HU and EX therapies may diminish the baseline activity of plasma lipids as compared to untreated children with SCD. In addition, sPLA2-treatment of the plasma 12 hours prior to the devlopment of ACS increased the amount of bioactive lipids released. Moreover, the amount of lipid priming activity was significantly increased during ACS as compared to baseline and during VOC. These preliminary results support the concept that the pathogenesis of ACS involves sPLA2 activity, which generates bioactive lipids that may provoke ACS, and need to be extended through the recruitment of more patients and completion of a multi-institutional trial.

Lipid priming activity in children with SCD

Group/Clinical StatusBaselineVOCACS
Units are nmol O2/min; † = p≤0.05 versus Baseline and VOC. 
SCD 1.8±0.8 1.3±0.1 2.3±0.2† 
SCD + HU 1.6±0.2 1.4±0.3 no data 
SCD + EX 1.5±0.2 1.8±0.2 no data 
Group/Clinical StatusBaselineVOCACS
Units are nmol O2/min; † = p≤0.05 versus Baseline and VOC. 
SCD 1.8±0.8 1.3±0.1 2.3±0.2† 
SCD + HU 1.6±0.2 1.4±0.3 no data 
SCD + EX 1.5±0.2 1.8±0.2 no data 

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