Effect of fasting on hyperoxic lung injury in mice. The role of glutathione

Fasted mice exposed to 100% oxygen have more lung damage and die sooner than do fed mice. The mechanism responsible for this phenomenon has not been identified. We performed the following experiments to test the hypothesis that reduced glutathione content in lung tissue of fasted mice contributes to the increased susceptibility to hyperoxic lung damage. First, air-exposed mice were fasted for as long as 3 days. They had little change in lung levels of superoxide dismutase (SOD) or catalase, but they had a 41% decrease in glutathione by Day 3 (p < 0.001). Second, fed mice and fasted mice were exposed to 100% oxygen for as long as 4 days. Both groups had nearly identical values of lung SOD and catalase, but the fasted mice had lower levels of glutathione (p < 0.001). Third, fed mice received the glutathione synthesis inhibitor buthionine sulfoximine (BSO; 20 mM) in their drinking water for 2 wk and were then exposed to either air or 100% oxygen. Air-exposed mice receiving BSO for 14 days had no change in lung SOD content, a 43% increase in catalase (p < 0.001), and a 41% decrease in glutathione (p < 0.01). Oxygen-exposed, BSO-treated mice had no change in SOD and an increase in catalase, but lower glutathione levels, more deaths, and increased lung damage on Day 3 (BAL protein: 1.72 ± 0.21 versus 0.94 ± 0.08 mg/ml; p < 0.01) than did diluent-treated mice. Fourth, fasted mice were given liposomes containing glutathione intratracheally. When exposed to air, they had smaller decreases in lung glutathione levels than did fasted mice receiving either nothing or liposomes containing PBS. When exposed to 100% oxygen, they had higher lung glutathione levels on Days 1, 2, and 3, fewer deaths, and lower BAL protein values on Day 3 than did the untreated fasted mice. Only partial protection was achieved after glutathione administration because the liposomes localized to the left lung. These results support our hypothesis that the increased susceptibility of fasted mice to hyperoxic lung damage may be due to a reduced lung content of glutathione.