title: Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality.
abstract: Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.
authors.affiliation: Vascular Therapeutics Section, Cardiovascular Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA. gkato@mail.nih.gov
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: Sabrina
authors.initials: S
authors.lastname: Martyr
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.forename: James S
authors.initials: JS
authors.lastname: Nichols
authors.forename: Wynona A
authors.initials: WA
authors.lastname: Coles
authors.forename: Lori A
authors.initials: LA
authors.lastname: Hunter
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Brennan
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000097:blood* / Q000187:drug effects; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D012995:Solubility; D016019:Survival Analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D006918:Hydroxyurea