D: Hypoxia-mediated induction of endothelial cell interleukin-1a. An autocrine mechanism promoting expression of leukocyte adhesion molecules on the vessel surface

Tissue injury that accompanies hypoxemia/reoxygenation shares features with the host response in inflammation, sug-gesting that cytokines, such as IL-1, may act as mediators in this setting. Human endothelial cells (ECs) subjected to hyp-oxia (Po2 12-14 Torr) elaborated IL-1 activity into condi-tioned media in a time-dependent manner; this activity was completely neutralized by an antibody to IL-la. Production of IL-1 activity by hypoxic ECs was associated with an increase in the level ofmRNA for IL-ia, and was followed by induction of endothelial-leukocyte adhesion molecule-1 and enhanced ex-pression of intercellular adhesion molecule-1 (ICAM-1) during reoxygenation. During reoxygenation there was a three- to five-fold increased adherence of leukocytes, partly blocked by anti-bodies to endothelial-leukocyte adhesion molecule-1 and ICAM-1. Suppressing endothelial-derived IL-1, using either antibodies to IL-la, specific antisense oligonucleotides or the IL-1 receptor antagonist, decreased leukocyte adherence to reoxygenated ECs, emphasizing the integral role of IL-1 in the adherence phenomenon. Mice subjected to hypoxia (Po2 30-40 Torr) displayed increased plasma levels of IL-la, induction of IL-ia mRNA in the lung, and enhanced expression of ICAM-1 in pulmonary tissue compared with normoxic con-trols. These data suggest that hypoxia is a stimulus which in-duces EC synthesis and release of IL-la, resulting in an auto-crine enhancement in the expression of adhesion molecules. (J