Abstract
Lipoxin A4 (LXA4) has been reported to reduce inflammation in experimental subarachnoid hemorrhage (SAH), but the mechanism remains unclear. In this study, we investigated the role of LXA4 in inflammation-mediated cerebrovascular endothelial dysfunction and the potential mechanism after SAH. SAH was induced by endovascular perforation in male Sprague-Dawley rats, and recombinant LXA4 was injected intracerebroventricularly 1.5 h after the operation. The expression changes in the markers of endothelial dysfunction (endothelial microparticles and nitric oxide) were analyzed by flow cytometry or Nitric Oxide (NO) assay kit. Microflow in the cerebral cortex was assayed by laser speckle contrast imaging. Neutrophil infiltration was observed by a marker of leukocyte activity (myeloperoxidase, MPO) that colocalized with a specific marker of endothelial cells (von Willebrand factor, VWF). The expression of LXA4 and its downstream molecules, formyl peptide receptor 2 (FPR2), extracellular signal-regulated kinase (ERK1/2), nuclear factor-κB (NF-κB), matrix metalloproteinase-9 (MMP9), and the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), leukocyte adhesion molecule (intercellular adhesion molecule-1, ICAM-1) and MPO were measured either by Western blot or enzyme-linked immunosorbent assay (ELISA). SAH resulted in endothelial dysfunction and a reduction in microflow in the cerebral cortex. The expression of LXA4 was decreased, and the expression of pro-inflammatory factors (NF-κB, MMP9, ICAM-1, MPO) and cytokines (TNF-α, IL-1β, IL-6) was increased after SAH. The administration of LXA4 significantly ameliorated endothelial dysfunction, recovered microflow, and suppressed the inflammation and infiltration of neutrophils in SAH rats. The underlying mechanism of this outcome may involve the LXA4/FPR2/ERK1/2 pathway. LXA4 might be a promising candidate for acute SAH treatment.