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

Abstract

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.

Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation

“…The Adm gene product is a multifunctional regulatory peptide implicated among others in the cellular response to inflammation and induction of angiogenesis. In accordance with our results, Adm expression is upregulated by hypoxia in lung tissue of rats both in vitro and in vivo (27). Ntrk2, encoding the receptor for brain-derived neurotrophic factor, has also been shown to be elevated at both mRNA and protein levels in hypoxic (8% O 2 ; 6 h) vs. normoxic rat lungs (28).…”

Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats

“…AM infusion significantly attenuated these abnormalities, suggesting that AM ameliorates LPS-induced acute lung injury in rats. We also demonstrated that the circulating level of AM was significantly increased after intratracheal instillation of LPS, which is consistent with previous observations that AM expression is increased in animals and humans with acute lung injury (1,46). In the present study, AM infusion caused a significant additional increase in the circulating level of AM in rats subjected to LPS instillation.…”

Therapeutic strategies in pneumonia: going beyond antibiotics

“…The crucial role of adrenomedullin in protecting vascular barrier integrity was underscored by demonstrating that mice deficient in adrenomedullin, CRLR or other components of the adrenomedullin signalling pathway die prematurely due to hydrops fetalis [63][64][65][66]. Furthermore, inflammatory conditions such as sepsis or acute lung injury increased adrenomedullin expression [67][68][69], and the inflammatory response and organ damage in mice heterozygous for the adrenomedullin gene were aggravated upon LPS challenge [70]. Treatment with exogenous adrenomedullin improved pulmonary barrier dysfunction caused by different stimuli such as hydrogen peroxide, LPS or Staphylococcus aureus α-toxin and was protective against ventilator-induced lung injury in mice with and without pneumonia [61,[71][72][73][74].…”