Background:
2-Methoxyestradiol (2ME), a natural 17-β
estradiol metabolite, is a potent
anti-inflammatory agent, but its effect on
ischemia/reperfusion (IR)-induced acute
lung inflammation remains unknown.
Annexin A1 (AnxA1), a
glucocorticoid-regulated
protein, is effective at inhibiting neutrophil transendothelial migration by binding the
formyl peptide receptors (FPRs). We aimed to investigate whether 2ME upregulates the expression of AnxA1 and protects against IR-induced lung damage. Methods: IR-mediated acute
lung inflammation was induced by
ischemia for 40 min followed by reperfusion for 60 min in an isolated, perfused rat lung model. The rat lungs were randomly treated with vehicle or 2ME, and the functional relevance of AnxA1 was determined using an anti-AnxA1 antibody or BOC2 (a pan-receptor antagonist of the FPR). In vitro, human primary alveolar epithelial cells (HPAECs) and rat neutrophils were pretreated with 2ME and an AnxA1
siRNA or anti-AnxA1 antibody and subjected to
hypoxia-reoxygenation (HR). Results: 2ME significantly decreased all lung
edema parameters, neutrophil infiltration, oxidative stress, proinflammatory
cytokine production, lung cell apoptosis,
tight junction protein disruption, and lung tissue injury in the IR-induced acute
lung inflammation model. 2ME also increased the expression of the AnxA1
mRNA and
protein and suppressed the activation of nuclear factor-κB (NF-κB). In vitro, 2ME attenuated HR-triggered NF-κB activation and
interleukin-8 production in HPAECs, decreased transendothelial migration,
tumor necrosis factor-α production, and increased apoptosis in neutrophils exposed to HR. These protective effects of 2ME were significantly abrogated by BOC2, the anti-AnxA1 antibody, or AnxA1
siRNA. Conclusions: 2ME ameliorates IR-induced acute
lung inflammation by increasing AnxA1 expression. Based on these results, 2ME may be a promising agent for attenuating IR-induced
lung injury.