Relationship between lung injury and lung lipid peroxidation caused by recurrent endotoxemia

We compared the relationship between lung lipid peroxidation and the histologic and physiologic changes seen after repeated doses of low dose endotoxin in unanesthetized sheep. Thirty-two sheep with lung lymph fistula were given from 1 to 10 doses of 1 micrograms/kg Escherichia coli endotoxin, 12 h apart. Animals were killed 5 h after 1, 3, 5, or 9 doses of endotoxin or 3 to 5 days after the tenth dose of endotoxin. The lipid peroxidation process was monitored by circulating conjugated dienes and lung tissue malondialdehyde (MDA) content. We found that conjugated dienes and MDA were increased after one dose of endotoxin corresponding in time with the increased prostanoid production and increased permeability. Acute lung inflammation was also evident histologically. Lipid peroxidation was not increased, however, when 3 to 7 doses were given. The permeability change was also markedly attenuated whereas severe lung inflammation was still present on histologic examination. After 9 doses, we noted a fourfold increase in lung tissue MDA that corresponded histologically with a marked mononuclear cell infiltration. Physiologic changes included a sustained 50% increase in oxygen consumption. However, lung lymph flow was not increased, again, reflecting lung inflammation with no change in lung vascular permeability. The MDA remained increased 5 days after the last dose of endotoxin along with a marked lung mononuclear cell infiltration. The lung MDA content corresponded with the level of increase in VO2, but not with changes in pulmonary vascular permeability. Conjugated dienes were increased only after the first injection of endotoxin. The lung lipid peroxidation process does not appear to correspond to physiologic or histologic lung changes after recurrent exposures to endotoxin.