Differing effects of nitrogen mustard and hydroxyurea on lung O2 toxicity in adult sheep

We measured the effects of leukocyte depletion on the pulmonary response to breathing 100% O2 in adult sheep, using two dissimilar agents. A group of eight sheep received 4.0 g/day of hydroxyurea for 4 to 6 days, and six sheep received two to four doses of 0.4 mg/kg of nitrogen mustard before exposure to 100% O2. A group of seven sheep breathed 100% O2 with no drug treatment. A group of five control sheep breathed compressed air for 96 h. Hydroxyurea selectively reduced circulating neutrophils (602 +/- 245 neutrophils, 2,537 +/- 394 lymphocytes per mm3), and nitrogen mustard decreased both circulating neutrophils (633 +/- 326) and lymphocytes (521 +/- 129). In untreated sheep breathing 100% O2, survival time was 92.6 +/- 3.4 h and postmortem blood-free lung water to dry lung ratio was 4.4 +/- 0.2. Hydroxyurea significantly delayed the onset of oxygen toxicity as measured by changes in lung lymph flow, PaO2, PaCO2, and time to respiratory failure (111.8 +/- 7.7 h), although the degree of final lung injury was unchanged and postmortem lung water was elevated (5.3 +/- 0.3). Nitrogen mustard shortened the time to hypoxemia, and CO2 retention and decreased time to respiratory failure (84.0 +/- 4.3 h). Neutrophils were markedly reduced but not absent in the lungs of both groups of leukocyte-depleted sheep. We conclude that neutrophils are not essential for the full expression of lung O2 toxicity in adult sheep. Secondary effects of hydroxyurea and nitrogen mustard appear to influence the rate of development, but not the outcome of oxygen toxicity, by effects independent of leukocyte depletion.