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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1555-1560
Sickle Cell Acute Chest Syndrome: Pathogenesis and Rationale for
Treatment
Marie J. Stuart and
B.N. Yamaja Setty
From the Department of Pediatrics and the Cardeza Foundation for
Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
Acute chest syndrome (ACS) is a leading cause of death in sickle
cell disease (SCD). Our previous work showed that hypoxia enhances the
ability of sickle erythrocytes to adhere to human microvessel
endothelium via interaction between very late activation antigen-4
(VLA4) expressed on sickle erythrocytes and the endothelial adhesion
molecule vascular cell adhesion molecule-1 (VCAM-1). Additionally,
hypoxia has been shown to decrease the production of nitric oxide (NO)
which inhibits VCAM-1 upregulation. Based on these observations, we
hypothesize that during ACS, the rapidly progressive clinical course
that can occur is caused by initial hypoxia-induced pulmonary
endothelial VCAM-1 upregulation that is not counterbalanced by
production of cytoprotective mediators, including NO, resulting in
intrapulmonary adhesion. We assessed plasma NO metabolites and soluble
VCAM-1 in 36 patients with SCD and 23 age-matched controls. Patients
with SCD were evaluated at baseline (n = 36), in vaso-occlusive
crisis (VOC; n = 12), and during ACS (n = 7). We observed marked
upregulation of VCAM-1 during ACS (1,290 ± 451 ng per mL; mean ± 1 SD) with values significantly higher than controls (P < .0001) or patients either in steady state or VOC (P < .01).
NO metabolites were concomitantly decreased during ACS (9.2 ± 1.5 nmol/mL) with values lower than controls (22.2 ± 5.5), patients
during steady state (21.4 ± 5.5), or VOC (14.2 ± 1.2) (P < .0001). Additionally, the ratio of soluble VCAM-1 to NO metabolites
during ACS (132.9 ± 46.5) was significantly higher when compared with
controls (P < .0001) or patients either in steady state or
VOC (P < .0001). Although hypoxia enhanced in vitro sickle
erythrocyte-pulmonary microvessel adhesion, NO donors inhibited this
process with concomitant inhibition of VCAM-1. We suggest that in ACS
there is pathologic over expression of endothelial VCAM-1. Our
investigations also provide a rationale for the therapeutic use in ACS
of cytoprotective modulators including NO and dexamethasone, which
potentially exert their efficacy by an inhibitory effect on VCAM-1 and
concomitant inhibition of sickle erythrocyte-endothelial adhesion.
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