RELEVANCE OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-ALPHA IN THE PATHOGENESIS OF HYPOXIA-RELATED ORGAN FAILURE

Tumour necrosis factor-alpha (TNF) and Interleukin-1-alpha (IL-1) are both cytokines which are known to be released by stimulated macrophage s during septic events. Because of their influence on the function of the vascular endothelium, TNF and IL-1 contribute to the pathogenesis of hypoperfusion and organ dysfunction. The finding of elevated cytoki ne levels in patients with hypoxic organ failure, suggesting a relatio n between systemic oxygen supply and humoral mechanisms, led us to per form laboratory investigations on the relevance of TNF and IL-1 for th e pathogenesis of hypoxia-related deterioration of the microcirculatio n. In vivo studies with anaesthetized rats demonstrated a synergism be tween hypoxaemia and endotoxaemia on the development of lethal organ f ailure. In vitro studies with human monocytes showed that a hypoxic at mosphere was not able to induce synthesis or release of TNF and IL-1, whereas re-oxygenation after hypoxia initiated a significant increase in TNF and IL-1 synthesis, probably mediated by oxygen radicals. Final ly, experiments with human endothelial cells established that hypoxia is able to induce high affinity receptors for TNF in a time- and dose- dependent manner. These studies demonstrate that hypoxia influences hu moral mechanisms which are known to contribute to the pathogenesis of vessel dysfunction, probably through a cytokine-dependent pathway of h ypoxia-related organ dysfunction.