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• W2092624150 abstract "Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease, progresses rapidly, causing life-threatening complications in patients receiving naturally toxic pyrrolizidine alkaloids, irradiation, conventional chemotherapy or myeloablative hematopoietic stem cell transplantation.1,2 Sinusoidal obstruction syndrome refers to a form of toxic liver injury characterized clinically by the development of jaundice, tender hepatomegaly, ascites, and sudden weight gain, and histologically by diffuse damage in the centrilobular zone of the liver. The most common cause of SOS is the myeloablative conditioning regimens (i.e. chemotherapy) used to prepare for hematopoietic stem cell transplantation in the treatment of malignancy. Sinusoidal obstruction syndrome has also been described in association with chemotherapeutic drugs such as gemtuzumab ozogamicin, actinomycin D, dacarbazine, cytosine arabinoside, mithramycin, and 6-thioguanine used at conventional doses, as well as with long-term use of the immunosuppressive agent azathioprine.2,3 The incidence of SOS following stem cell transplantation ranges from 5% to 70% according to various reports,2 but has been decreased to 30% or less with the advent of non-myeloablative conditioning and avoidance of cyclophophamide in myeloablative regimens.3,4 Most patients with mild or moderate SOS will recover. However, severe SOS carries a grave prognosis and typically runs a fulminant clinical course with acute liver failure, coagulopathy, and hepatorenal syndrome. In contrast, SOS after chemotherapy in a clinical context other than stem cell transplantation is rare. The use of oxisaliplatin for treatment of colorectal liver metastases has, however, recently been linked to the development of SOS.5 Chemotherapy-related hepatic lesions may limit extensive liver resection and may contribute to postoperative morbidity or mortality. The pathophysiologic events leading to the development of the histological changes seen in SOS were recently reported for a reproducible rat model of SOS prepared by treatment with monocrotaline, a pyrrolizidine alkaloid extracted from the plant genus Crotalaria.3 In this model, the primary site of toxic injury is liver sinusoidal endothelial cells (LSECs). Within 48 h of monocrotaline treatment, there is loss of fenestrations in LSECs, formation of gaps within and between them, and swelling or rounding up of LSECs. Red blood cells penetrate beneath the swollen LSECs, and blood begins to flow into the underlying space of Disse, with dissection of the sinusoidal lining cells. The sinusoidal lining cells comprising LSECs, Kupffer cells, and stellate cells slough and embolize distally, resulting in obstruction of the sinusoidal blood flow. The initial LSEC injury in this model can be attributed to depolymerization of F-actin through a reactive metabolite of monocrotaline. Since the actin cytoskeleton plays a major role in cell morphology, F-actin depolymerization results in rounding up of the LSECs. Injury to the LSECs followed by a series of biologic processes leads to circulatory compromise of centrilobular hepatocytes, fibrosis, and obstruction of liver blood flow.3 Biochemically, SOS has been associated with a decrease in protein C and anti-thrombin III levels, increased levels of plasminogen activator inhibitor-1, and a release of von Willebrand's factor. Some of these observations have led to pharmacological interventions involving low-dose heparin, AT III replacement, prostaglandin E1, recombinant tissue plasminogen activator, N-acetylcysteine, or defibrotide.4 Among these agents, defibrotide, a mixture of porcine-derived phosphodiester oligonucleotides, has been suggested to show promise for the prevention and treatment of SOS.6 Since SOS contributes to considerable morbidity and mortality, further understanding of its pathogenesis and development of therapeutic or preventive strategies are required. In this issue of the Journal of Gastroenterology and Hepatology, Narita and colleagues7 report a novel therapeutic candidate for the treatment of SOS. They demonstrate that the traditional Japanese kampo (herbal) medicine Dai-kenchu-to (DKT), and in particular one of its ingredients, processed ginger, has significant efficacy against SOS in monocrotaline-treated rats. Attenuated monocrotaline-induced liver injury induced by DKT is associated with decreases in neutrophil accumulation and hepatic mRNA expressions of cytokine-induced neutrophil chemoattractant (CINC) and intercellular adhesion molecule (ICAM)-1. However, DKT does not exhibit any protection against LSEC injury, which is considered the initial event in the development of SOS. Since LSEC injury begins 12 h after the monocrotaline treatment,3 when the first dose of DKT is administered via oral gavage, it is conceivable that DKT can not inhibit the initial event of SOS. Despite the ongoing LSEC injury that allowed red blood cells to enter into the extrasinusoidal space, DKT attenuates the coagulative necrosis of hepatocytes by inhibiting neutrophil accumulation. Narita et al.'s findings suggest that neutrophils play a critical role in the development of coagulative necrosis induced by monocrotaline. Liver injury mediated by neutrophils has been reported in a number of experimental models including hepatic ischemia-reperfusion, endotoxin shock, alcoholic hepatitis, or obstructive jaundice.8 The authors also speculate that the accumulated neutrophils elicit liver injury in response to monocrotaline. However, extravasation and migration into the hepatic parenchyma are prerequisites for neutrophil-mediated liver injury.8 It is only the extravasated neutrophils that generate reactive oxygen species, which promote substantial hepatocellular injury. Thus, DKT may reduce the numbers of extravasated neutrophils, although there is a lack of evidence to support this notion at present. Since the architecture of the sinusoids is destroyed by the administration of monocrotaline, it appears that distinguishing the extravasated neutrophils and the intra-sinusoidal neutrophils in the liver would be difficult. It is also difficult to ascertain whether the neutrophils extravasate from the sinusoids under such conditions since the neutrophils would attach to the hepatic parenchyma directly without transmigration. Nevertheless, the evidence presented suggests that DKT can inhibit neutrophil adhesion to the hepatic sinusoids, neutrophil extravasation into the hepatic parenchyma, and neutrophil-induced oxidant stress, although Narita et al. do not provide detailed insight into the mechanisms responsible for DKT protection against SOS. Moreover, Narita et al. provide evidence for protective effects of DKT for the first 2 days after monocrotaline treatment, referred to as the pre-SOS (0–48 h after monocrotaline administration).3 It remains to be seen whether DKT exhibits the same protective effects from the early SOS (days 3 to 5) as well as the late SOS (days 6 and 7). In summary, the work by Narita et al. has raised additional questions and provided important insights into the pathogenesis of SOS with respect to neutrophil-mediated liver injury during the pathological evolution of the disease. Therapeutic strategies aimed at preventing neutrophil-mediated liver injury have to take into consideration host-defence functions of neutrophils. Further studies will confirm a relevant role of neutrophils in the mechanisms of monocrotaline-induced liver injury, and could provide the evidence for the therapeutic potential of DKT in the treatment and prevention of SOS in a clinical context." @default.
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• W2092624150 title "A novel therapeutic strategy for liver sinusoidal obstruction syndrome" @default.
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