Leukocyte responses to hypoxic/ischemic conditions.

Ischemia is an interruption of oxygen and nutrient supply to a determined area of tissue for a period of time. Because of the heterogeneity of various tissues with regard to their microvascular flow reserve and oxidative capacity, as well as their markedly different metabolic needs, a single critical Po2 level below which ischemia occurs is unlikely. This is why there are variations of tolerance to hypoxia within and among organs. In general, when Pao2 reaches approximately 5 torr there is already evidence, in some organs, of altered cellular energetics. In addition, cessation of flow impairs the incoming transfer of nutrients such as glucose, and cells must depend on their own intracellular stores of carbon radicals, if available. Epidemiologic data suggest that there are deleterious effects of hypoxia on the immune system and that these effects result in increased susceptibility to infection. The histology of ischemic tissues demonstrates intravascular neutrophil (PMN) accumulation, vascular damage, and increased vascular permeability. Expression of PMN adhesion receptors is increased when oxygen is nearly completely removed from the medium. Expression of integrins on the cell surface is regulated by intracellular calcium; hypoxia causes a sustained and prolonged increase of intracellular calcium levels. Because both granule movement and functional expression of adhesion receptors on the cell surface are important in leukocyte motility, chemotaxis, and phagocytosis, these functions may be impaired by hypoxia. Exposure of a human macrophage cell line to nonlethal levels of hypoxia causes in vitro release of significant amounts of biologically active cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1 and IL-8, as well as expression of intercellular adhesion molecule-1 and bound and soluble receptors for TNF alpha. Hypoxia markedly decreases T-lymphocyte IL-2 messenger RNA, a key cytokine responsible for B-cell proliferation and immunoglobulin secretion.