Endothelial activation contributes to lung inflammatory disorders by inducing leucocyte recruitment to pulmonary parenchyma. Consequently, vascular-targeted
therapies constitute promising strategies for the treatment of inflammatory pathologies. In the present study, we evaluated the effect of 8,9-dehydrohispanolone-15,16-lactol
diterpene (DT) on lung endothelium during
inflammation. Lung endothelial cells pre-treated with DT and activated with
lipopolysaccharide (LPS) or tumour
necrosis factor-α (TNF-α) exhibited reduced expression of the pro-inflammatory
cytokines Cxcl10, Ccl5 and Cxcl1, whereas the anti-inflammatory molecules IL1r2 and
IL-10 were induced. Consistent with this result, DT pre-treatment inhibited nuclear factor κB (NF-κB) nuclear translocation, by interfering with IκBα phosphorylation, and consequently NF-κB transcriptional activity in endothelium activated by LPS or TNF-α. Furthermore, DT, probably through p38 signalling, induced transcriptional activation of genes containing
activator protein 1 (AP-1)-binding elements. Inhibition of p38 prevented IL1r2
mRNA expression in endothelium incubated with DT alone or in combination with LPS or TNF-α. Accordingly,
conditioned medium (CM) from these cells failed to stimulate leucocytes as measured by a reduction in adhesive ability of the leucocyte cell line J774 to
fibronectin (FN). Additionally, DT reduced the expression of the endothelial adhesion molecules
E-selectin,
vascular cell adhesion molecule 1 (VCAM-1) and
intercellular adhesion molecule 1 (ICAM-1) after activation. Similarly, expression of
VCAM-1 and
ICAM-1 molecules on the lung endothelial layer of C57/BL6 mice pre-treated with DT and challenged with LPS were unchanged. Finally, inhibition of vascular adhesion molecule expression by DT decreased the interaction of J774 cells with lung endothelial cells in an inflammatory environment. Our findings establish DT as a novel endothelial inhibitor for the treatment of inflammatory-related diseases triggered by Gram-negative bacteria or by the associated
cytokine TNF-α.