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Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS

¹Division of Oncology, Center for Applied Medical Research, University of Navarra; ²Department of Histology and Pathology; and ³Pulmonary Service, Clínica Universitaria; University of Navarra School of Medicine, Navarra, Spain

Submitted 20 August 2004 ; accepted in final form 23 November 2004

Adrenomedullin (ADM) is upregulated independently by hypoxia and LPS, two key factors in the pathogenesis of acute lung injury (ALI). This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O₂) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O₂). ADM expression was analyzed by in situ hybridization, Northern blot, Western blot, and RIA analyses. In the rat lung, combination of hypoxia and LPS treatments overcomes ADM induction occurring after each treatment alone. With in situ techniques, the synergistic effect of both stimuli mainly correlates with ADM expression in inflammatory cells within blood vessels and, to a lesser extent, to cells in the lung parenchyma and bronchiolar epithelial cells. In the in vitro model, hypoxia and hypoxia + LPS treatments caused a similar strong induction of ADM expression and secretion in epithelial and endothelial cell lines. In alveolar macrophages, however, LPS-induced ADM expression and secretion were further increased by the concomitant exposure to hypoxia, thus paralleling the in vivo response. In conclusion, ADM expression is highly induced in a variety of key lung cell types in this rat model of ALI by combination of hypoxia and LPS, suggesting an essential role for this mediator in this syndrome.

acute respiratory distress syndrome; endotoxin; alveolar macrophages; endothelial cells; type II pneumocytes

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