Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

Abstract

Abstract. Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P-selectin, rat endothelial cell antigen-1, CD34, and cleaved caspase-3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT-treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total-bilirubin (P=0.012), direct-bilirubin (P=0.007), indirect-bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT-treated than in control rats. The livers of MCT-treated rats were immunohistochemically positive for CD41 and P-selectin, suggesting platelet aggregates; for rat endothelial cell antigen-1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase-3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS.

A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome

“…This created gaps allowing red blood cells to enter the space of Disse and deteriorate the sinusoidal lining, all of which embolized and reduced sinusoidal blood flow. 24 Embolization in the space of Disse was further confirmed in a recent study by Hirata et al (2017) 25 ( Table 2). In the two other studies, DeLeve et al found that the loss of sinusoidal integrity is directly related to an increase in matrix metalloproteinase-9 (MMP-9) activity, which is reinforced by a decrease in nitric oxide (NO) production.…”

“…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.…”

The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP

“…A central pathological event under these conditions is a toxic destruction of hepatic sinusoidal endothelial cells, with sloughing and downstream occlusion of terminal hepatic venules. Extravasated platelet aggregation in the space of Disse (as observed in Mfsd1 KO and Glmp KO mice) was observed in a rat model for SOS (Hirata et al, 2017). Contributing factors are LSEC glutathione- and nitric oxide depletion.…”

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

“…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 ].…”