Platelet‐dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation‐induced cholestasis

Abstract

Background: Although it is well known that extrahepatic cholestasis induces liver damage, the mechanisms are still not completely understood. The aim of the present study was to evaluate the role of platelets and P-selectin in cholestasis-induced liver injury. Experimental approach: C57BL/6 mice underwent bile duct ligation (BDL) and pretreatment with an anti-GP1ba antibody, which depletes platelets, an anti-P-selectin antibody or a control antibody. Hepatic platelet and leukocyte recruitment as well as microvascular perfusion were determined by intravital fluorescence microscopy. Key results: BDL caused significant liver damage and sinusoidal perfusion failure. BDL further induced hepatic platelet accumulation with widespread intravascular platelet aggregates, increased platelet adhesion in postsinusoidal venules and massive platelet accumulation in liver sinusoids. Administration of the anti-GP1ba antibody reduced systemic platelet count by 90%. Depletion of platelets in BDL mice not only abolished accumulation and adhesion of platelets in sinusoids and venules but also restored sinusoidal perfusion and reduced liver enzymes by more than 83%. Platelet depletion further reduced BDLassociated sinusoidal leukocyte accumulation by 48% although leukocyte-endothelium interactions in venules were not affected. Immunoneutralization of P-selectin also inhibited hepatic microvascular accumulation of platelets and leukocytes, and protected against cholestasis-provoked hepatocellular damage. Conclusions and implications: Platelets play an important role in BDL-induced liver injury by promoting leukocyte recruitment and deteriorating microvascular perfusion. Moreover, our findings demonstrate that cholestasis-induced accumulation of platelets is mediated by P-selectin. Thus, targeting platelet accumulation may be a useful strategy against liver damage associated with obstructive jaundice.

Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice

“…Indeed, in experimental settings where neutrophils are definitively linked to hepatotoxicity, the interaction of platelets and neutrophils worsens liver damage. [46][47][48] We found that platelet depletion tended to reduce accumulation of neutrophils within necrotic foci in APAP-treated mice. It is worth noting, however, that the role of neutrophils in APAP hepatotoxicity continues to be debated.…”

Measuring and interpreting platelet-leukocyte aggregates

“…Nicotinamide adenine dinucleotide phosphate oxidase 2 might also play a role in mediating platelet-neutrophil interactions in this setting (61). In another sterile injury model, following bile duct ligation-induced cholestasis, platelet aggregates support leukocyte recruitment to liver sinusoids and postsinusoidal venules involving P-selectin (63). Hence, these studies emphasise a mechanistic link between platelet-leukocyte interactions and leukocyte recruitment followed by tissue damage in a wide range of inflammatory liver disease.…”

Platelet functions beyond hemostasis

“…Given the number and variety of bioactive substances secreted by platelets (Table 1), it is unsurprising that they have been implicated in the development or severity of an array of disorders (Table 2) [11,[24][25][26][27][28][29][30][31][32][33][34][35][36]. Some of these disorders may appear obvious (thrombosis and restenosis) but others may not (psoriasis and migraine).…”