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Sickle cell acute chest syndrome: pathogenesis and rationale for treatment.
Blood 1999; 94(5):1555-60Blood

Abstract

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.

Authors+Show Affiliations

Department of Pediatrics and the Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA 19107, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10477680

Citation

Stuart, M J., and B N. Setty. "Sickle Cell Acute Chest Syndrome: Pathogenesis and Rationale for Treatment." Blood, vol. 94, no. 5, 1999, pp. 1555-60.
Stuart MJ, Setty BN. Sickle cell acute chest syndrome: pathogenesis and rationale for treatment. Blood. 1999;94(5):1555-60.
Stuart, M. J., & Setty, B. N. (1999). Sickle cell acute chest syndrome: pathogenesis and rationale for treatment. Blood, 94(5), pp. 1555-60.
Stuart MJ, Setty BN. Sickle Cell Acute Chest Syndrome: Pathogenesis and Rationale for Treatment. Blood. 1999 Sep 1;94(5):1555-60. PubMed PMID: 10477680.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sickle cell acute chest syndrome: pathogenesis and rationale for treatment. AU - Stuart,M J, AU - Setty,B N, PY - 1999/9/9/pubmed PY - 1999/9/9/medline PY - 1999/9/9/entrez SP - 1555 EP - 60 JF - Blood JO - Blood VL - 94 IS - 5 N2 - 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. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/10477680/Sickle_cell_acute_chest_syndrome:_pathogenesis_and_rationale_for_treatment_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&amp;pmid=10477680 DB - PRIME DP - Unbound Medicine ER -