Superoxide production by peripheral blood monocytes during sustained endotoxaemia in sheep

1. We have studied the time course of the numbers of arterial monocytes and their superoxide anion (O2-) production in a chronically instrumented sheep model of subacute endotoxaemia induced by a continuous intravenous infusion of Escherichia coli lipopolysaccharide (20 ng min-1 kg-1). 2. Four out of 11 animals died from irreversible respiratory and cardiovascular failure within 21 h of the start of lipopolysaccharide administration ('non-survivors'), whereas in the seven surviving sheep ('survivors') there was a persistence of decreased systemic vascular resistance, systemic hypotension, pulmonary hypertension, anorexia and lethargy. 3. O2- generation by isolated monocytes was measured by the O2- dismutase-inhibitable reduction of ferricytochrome c after stimulation with phorbol myristate acetate (100 ng/ml) or opsonized zymosan (3 mg/ml). Basal mean value of phorbol myristate acetate-stimulated O2- production was significantly (P = 0.008) higher for non-survivors (31.3 +/- 8.8 nmol 30 min-1 10(-6) cells; n = 4) than for survivors (6.2 +/- 2.3 nmol 30 min-1 10(-6) cells; n = 7). 4. For both survivors and non-survivors, monocyte counts and phorbol myristate acetate-stimulated O2- production increased over time to reach in survivors a plateau after 2 days of continuous lipopolysaccharide infusion. Similar results were obtained when monocytes were stimulated for O2- production with opsonized zymosan. 5. These results suggest that (1) increased O2- production by monocytes and monocytosis appear with a precise, delayed time course during the development of subacute endotoxaemia in sheep; and (2) a high stimulated O2- production by monocytes before lipopolysaccharide administration may represent a predictive factor for the subsequent respiratory failure and outcome of endotoxaemia.