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Eur J Cardiothorac Surg 2003;23:976-983
© 2003 Elsevier Science NL

Hypoxia and reoxygenation do not upregulate adhesion molecules and natural killer cell adhesion on human endothelial cells in vitro

^a Clinic for Cardiovascular Surgery, University Hospital Zürich, Rämistr. 100, F LAB 39, CH-8091 Zürich, Switzerland
^b Laboratory for Transplantation Immunology, University Hospital Zürich, Rämistr. 100, F LAB 39, CH-8091 Zürich, Switzerland

Received 22 October 2002; received in revised form 24 February 2003; accepted 27 February 2003.

^* Corresponding author. Tel.: +41-1-255-1111; fax: +41-1-255-4445
e-mail: christine.maurus{at}usz.ch

Objectives: Ischemia/reperfusion injury is characterized by endothelial cell activation leading to increased expression of adhesion molecules such as inter-cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, endothelial- and platelet-selectin (E- and P-selectin), and to the subsequent recruitment of leukocytes. The aim of the present study was to investigate the respective effects of a proinflammatory cytokine (tumor necrosis factor alpha , TNF-), hypoxia and/or reoxygenation on adhesion molecule expression and natural killer (NK) cell adhesion in an in vitro model of I/R. Methods: Human aortic endothelial cells (HAEC) were stimulated in vitro for 8h with TNF- (1000 U/ml) and exposed to hypoxia (1% O₂), reoxygenation (21% O₂) or different combinations thereof. Cell surface expression of ICAM-1, VCAM-1 and E-/P-selectin on HAEC was analyzed by flow cytometry, and culture supernatants were tested for soluble adhesion molecules by ELISA. Rolling adhesion of NK cells on HAEC was determined using a rotating assay. Results: Untreated HAEC constitutively expressed ICAM-1 on their surface but neither expressed E-/P-selectin, VCAM-1, nor shedded soluble adhesion molecules. Exposure of HAEC to hypoxia or hypoxia and reoxygenation did not upregulate cell surface expression or shedding of adhesion molecules. In contrast, TNF- significantly upregulated cell surface expression of ICAM-1, VCAM-1, and E-/P-selectin and led to the shedding of ICAM-1 and E-selectin. Combined treatment of HAEC with TNF-, hypoxia and reoxygenation reduced E-/P-selectin surface expression and enhanced E-selectin shedding, but did not further influence ICAM-1 and VCAM-1. Soluble VCAM-1 was not detected. NK cell adhesion on HAEC increased 4-fold after TNF- stimulation, but was not affected by hypoxia or hypoxia and reoxygenation. Conclusions: Both the expression of endothelial adhesion molecules and rolling NK cell adhesion was upregulated by TNF- but not by hypoxia alone or hypoxia followed by reoxygenation supporting the view that anti-inflammatory treatment may reduce ischemia/reperfusion injury.

Key Words: Ischemia/reperfusion injury • Hypoxia/reoxygenarion • Human aortic endothelial cells • Adhesion molecules • Natural killer cells • Tumor necrosis factor alpha

Abbreviations: HAEC, human aortic endothelial cells • NK cells, natural killer cells • ICAM, inter-cellular adhesion molecule • VCAM, vascular cell adhesion molecule • E-selectin, endothelial selectin • P-selectin, platelet selectin • TNF-, tumor necrosis factor alpha • H/R, hypoxia/reoxygenation • PBMC, peripheral blood mononuclear cells