Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space

Abstract

Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.

Prognostic factors for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: a multicenter study in China

“…Thrombocytopenia have not been observed in most PAinduced HSOS and oxaliplatin-induced HSOS (5,18,(29)(30)(31). Interestingly, platelet aggregation in Disse's space is involved in the development of SOS (32,33), and thus the inhibition of platelet aggregation with phosphodiesterase III inhibitors can attenuate rat sinusoidal obstruction syndrome (34). In the pathogenesis of HSOS, LSECs are damaged by toxic metabolites of PAs, pyrroleprotein adducts (PPAs) in PA-induced HSOS (35); while toxic damage of LSECs may result from increased metabolic activation by LSECs (dacarbazine) or decreased detoxification by glutathione (GSH) (azathioprine and the cyclophosphamide metabolite, acrolein).…”

Pretreatment with a Phosphodiesterase-3 Inhibitor, Milrinone, Reduces Hepatic Ischemia-Reperfusion Injury, Minimizing Pericentral Zone-Based Liver and Small Intestinal Injury in Rats

“…Sinusoidal capillarization impedes SEC function via the fenestrations [ 46 ]. CD34 is an intercellular adhesion protein often used to detect the presence of sinusoidal capillarization [ 47 – 50 ]. Previous reports revealed that CD34 expression occurred simultaneously with SEC injury, hepatocyte apoptosis, and liver functional impairment [ 47 , 49 , 50 ].…”

“…CD34 is an intercellular adhesion protein often used to detect the presence of sinusoidal capillarization [ 47 – 50 ]. Previous reports revealed that CD34 expression occurred simultaneously with SEC injury, hepatocyte apoptosis, and liver functional impairment [ 47 , 49 , 50 ]. In our hepatic IRI model, sinusoidal capillarization occurred mainly in zone 3 and may have affected hepatic parenchymal injury, including vacuolization, necrosis, and apoptosis, which developed in zone 3 compared with zone 1.…”

“…One possible mechanism for this may be associated with reduced red blood cell velocity induced by deteriorated SEC function. Regarding the congestion at zone 3, we previously used a VOD model, characterized by severe congestion and SEC injury in zone 3, to demonstrate that extravasated platelet aggregation (EPA) occurred after sinusoidal endothelial denuding, and platelet activation resulted in the release of PAI-1 [ 49 , 50 ]. PAI-1 negatively regulates hepatocyte proliferation by inhibiting urokinase-type plasminogen activator, which activates hepatocyte growth factor [ 56 , 57 ].…”

A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome

“…Even those that used other small rodents varied the dosage of MCT. 29,33 Moreover, after 2009, many studies using rats switched to 90 mg/kg doses, although still citing the original model by DeLeve et al 13,14,[25][26][27][28][34][35][36][37][38][39] However, as the first study to use this dosage, briefly summarize SOS development in their model in four phases over seven days-early toxicity on day 1, severe sinusoidal changes and coagulative necrosis on days 2-3, development of fibrosis on days 4-6, and almost complete recovery on day 7. 37 This four-phase course of SOS produced similar histopathological changes to human SOS (day 2) and matches the ten-day staging of the 160 mg/kg model proposed by DeLeve et al (Figure 1), a result that directly opposes the "dosage window" of 100-200 mg/kg.…”