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 syndrom
