Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Selexipag Improves Lipopolysaccharide-Induced ARDS on C57BL/6 Mice by Modulating the cAMP/PKA and cAMP/Epac1 Signaling Pathways
Hongliu ChenYing ShenYi LiangYing QiuMeili XuChaoqian Li
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2022 Volume 45 Issue 8 Pages 1043-1052


Selexipag, a long-acting and selective prostacyclin (PGI2) IP receptor agonist, has in aged rats with stroke revealed effects of inhibiting inflammation, ameliorating damage to the blood-brain barrier, and alleviating oxidative stress. However, in the case of acute respiratory distress syndrome (ARDS) characterized by diffuse alveolar damage and lung capillary endothelial injury, its effects yet remain unknown. In this study, we investigated effects of the prophylaxis by Selexipag on a mouse model of ARDS established by the lipopolysaccharide (LPS) challenge and potential mechanism. Compared to the LPS-challenged mice, the LPS-challenged mice with the prophylaxis by 0.5 or 1 mg/kg of Selexipag exhibited significantly alleviated lung histological manifestations, reduced protein leakage, decreased levels of interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1), diminished expressions of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) mRNA, noticeably increased expressions of zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) protein, escalated lung cAMP levels, and raised levels of lung relative phosphorylated-protein kinase A catalytic subunit (p-PKA C) at Thr197 and exchange protein activated by cAMP 1 (Epac1) protein. These results suggest that, through suppressing inflammation and reducing vascular endothelial damage, Selexipag can effectively ameliorate the LPS-induced ARDS on mice. The lung cAMP and its downstream signaling modules, PKA and Epac1, possibly constitute the main regulative molecular mechanism. Selexipag appears to hold promise to become a new potential therapeutic option for ARDS.

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