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Physiologic, Biochemical, and Imaging Characterization of Acute Lung Injury in Mice

Departments of Internal Medicine and Radiology, Washington University School of Medicine; and the Mallinckrodt Institute of Radiology, St. Louis, Missouri

Correspondence and requests for reprints should be addressed to Daniel P. Schuster, M.D., University Box 8225, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: daniel.schuster{at}wustl.edu

Rationale: Most models of acute lung injury in mice have yet to be fully characterized. Objectives: To directly compare and contrast endotoxin and oleic acid models of acute lung injury in mice in terms of their physiologic, biochemical, histopathologic, and imaging manifestations. Methods: Survival studies, lung weights, x-ray computed tomographic scanning, light and electron microscopy, bronchoalveolar lavage, lung uptake of (¹⁸F)fluorodeoxyglucose, tissue myeloperoxidase, arterial blood gases, mean arterial pressure, and lung tissue prostanoids were measured in separate groups of C57Bl/6 mice (normal animals, endotoxin only [20 µg/g], oleic acid only [0.15 µl/g], or endotoxin + oleic acid). Results: Endotoxin alone caused only mild pulmonary neutrophilic inflammation with little functional or structural damage to the alveolar architecture. In contrast, oleic acid caused severe alveolar damage with the development of alveolar edema of the increased-permeability type with associated abnormalities in gas exchange. When given together, endotoxin and oleic acid acted synergistically to increase pulmonary edema and to worsen gas exchange and hemodynamics, thereby increasing mortality. This synergism was significantly attenuated by the prior administration of the endotoxin antagonist E5564 (eritoran). Conclusions: Under the conditions of these studies, only mice exposed to oleic acid showed both structural and functional characteristics of acute lung injury. Nevertheless, endotoxin had potent synergistic physiologic effects that increased mortality. Overall, these models, which can be translated to genetically altered mice, are amenable to study with state-of-the-art imaging techniques, and with experimental interventions that can probe the underlying mechanisms of injury.

Key Words: fluorodeoxyglucose F18 • mice • positron-emission tomography • respiratory distress syndrome (adult)

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