부산대학교 도서관

Unregulated inflammation underlies many diseases, including sepsis. Much interest lies in targeting anti-inflammatory mechanisms to develop new treatments. One such target is the anti-inflammatory protein annexin A1 (AnxA1) and its receptor, FPR2/ALX. Using intravital videomicroscopy, we investigated the role of AnxA1 and FPR2/ALX in a murine model of endotoxininduced cerebral inflammation [intraperitoneal injection of lipopolysaccharide (LPS)]. An inflammatory response was confirmed by elevations in proinflammatory serum cytokines, increased cerebrovascular permeability, elevation in brain myeloperoxidase, and increased leukocyte rolling and adhesion in cerebral venules of wild-type (WT) mice, which were further exacerbated in AnxAl-nuU mice. mRNA expression of TLR2, TLR4, MyD-88, and Ly96 was also assessed. The AnxAl-mimetic peptide, AnXA1Ac2-26 (100 µg/monse, ~33 µmol) mitigated LPS-induced leukocyte adhesion in WT and AnxAl-null animals without affecting leukocyte rolling, in comparison to saline control. AnxA1Ac2-26 effects were attenuated by Boc2 (pan- FPR antagonist, 10 µg/monse, -12 nmol), and by minocycline (2.25 mg/mouse, ~6.3 nmol). The nonselective Fpr agonists, fMLP (6 µg/mouse, ~17 nmol) and AnXA1Ac2-26, and the Fpr2-selective agonist ATLa (5 µg/ mouse, ~11 nmol) were without effect in Fpr2/3 -/- mice. In summary, our novel results demonstrate that the AnxA1/FPR2 system has an important role in effecting the resolution of cerebral inflanunation in sepsis and may, therefore, provide a novel therapeutic target. [ABSTRACT FROM AUTHOR]