Antioxidant enzymes are induced during recovery from acute lung injury

Objective: To determine the contribution of the pulmonary antioxidant defen se enzymes of the hexose monophosphate (HMP) shunt and glutathione systems to recovery from oxidant-mediated lung injury in an animal model shown to c losely resemble the clinical syndrome of acute respiratory distress syndrom e. Design: Prospective, controlled laboratory study on phorbol myristate aceta te (PMA)-induced lung injury in rabbits. Setting: Animal research laboratory. Subjects: Rabbits were injected with PMA (80 mu g/kg) for 3 consecutive day s. Control animals received normal saline, Measurements and Main Results: Lungs were harvested at 24, 48, 72, and 96 h rs (n = 5/time point) after PMA injection or after the third injection of n ormal saline in control animals (n = 6), The cytosolic fraction from lung a nd bronchial alveolar lavage (BAL) fluid was used for measurements of HMP s hunt and glutathione enzymes. Pulmonary activity peaked at 48 hrs post-PMA injury with a 40% increase in glucose-6-phosphate dehydrogenase activity an d a 32% increase in 6-phosphogluconate dehydrogenase activity over control levels, BAL activity was maximal at 72 hrs with an increase of 98% in gluco se-6-phosphate dehydrogenase and 346% in 6-phosphogluconate dehydrogenase a ctivities, Glutathione peroxidase was maximally induced by 77% at 48 hrs in BAL and by 107% at 24 hrs in lung, Glutathione reductase activity did not increase significantly in either lung or BAL. Conclusions: The observed induction of the antioxidant enzymes in response to PMA suggests that both the HMP shunt and the glutathione systems contrib ute to the recovery phase of oxidant-mediated lung injury. The inability of natural host defenses to regenerate reduced glutathione may explain failur e of recovery from acute respiratory distress syndrome and suggests an aven ue for clinical intervention.