Background Liver sinosoidal endothelial cells (LSECs) are critical gatekeepers of sinusoidal homeostasis. They are the first impaired cells in response to liver injury and contribute to liver fibrosis. Our preliminary studies have shown that hepatic cyclooxygenase-2 (COX-2) expression was correlated with the severity of inflammation and fibrosis. The present study aimed to investigate the role of COX-2 on LSECs function and its underlying molecular mechanism.

Methods Liver fibrosis was induced by intraperitoneal injection of thioacetamide (TAA) or feeding 0.1% 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC)-containing diet. Mice with LSEC-specific deletion of Ptgs2 or treatment with the COX-2 inhibitors were studied in TAA and/or DDC diet-induced liver fibrosis model. The fibrosis severity, hepatic injury and inflammatory cell infiltration were evaluated. Primary human and murine LSECs were treated with TNFα, or pretreated with different reagents before stimulation. Cell response and target molecule were studied.

Results In both acute and chronic liver injury models, COX-2 expression was elevated and was co-stained with LYVE1, an LSEC-specific maker. In in vivo studies, LSEC-specific Ptgs2 deletion reduced liver fibrosis and hepatic inflammation. The down-regulated DEGs by Ptgs2 knockout were enriched in leukocyte chemotaxis, migration and adhesion. In in vitro studies, TNFα activated NF-κB signaling pathway and induced chemokines (CXCL1 and CCL2) and adhesion molecules (ICAM1 and VCAM1). These TNFα-induced effects could be potently suppressed by COX-2-PGE2-EP2 axis inhibitors. The pharmacologic effects of COX-2 were demonstrated by using specific inhibitors. Celecoxib and Etoricoxib, both are selective COX-2 inhibitors, were able to reduce hepatic fibrosis and inflammation.

Conclusions COX-2 expression in LSECs is up-regulated in liver fibrosis. Upon inflammatory stimulation, COX-2-PGE2-EP2 axis increases chemokines and adhesion molecules through the synergistic activation of NF-κB signaling pathway, leading to leukocyte recruitment and hepatic inflammation. Inhibition of COX-2 attenuates fibrosis and liver injury. The present study sheds light on the regulation of LSECs on leukocyte recruitment through a cyclooxygenase-2-dependent mechanism. Our results suggest COX-2 as a potential therapeutic target in the treatment of liver fibrosis.