Hepatic platelet accumulation in Fas-mediated hepatitis in mice

Ohtaki, Yuko; Yamaguchi, Kohei; Yu, Zhiqian; Kumamoto, Hiroyuki; Shimauchi, Hidetoshi; Iwakura, Yoichiro; Sugawara, Shunji; Endo, Yasuo

doi:10.1016/j.intimp.2009.04.016

Cited by 6 publications

(6 citation statements)

References 38 publications

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“…Collectively, the above observations suggest that platelets are highly specialized cells (or organic bodies) that have evolved in mammals, and that they perform their specialized functions efficiently and in a highly integrated manner. We recently found, in a murine hepatitis model, that platelet accumulation in the liver may be protective when the hepatitis is not severe, but harmful when the hepatitis is severe [53]. Interestingly, the present study showed that platelet depletion augmented Man-ALS.…”

Section: Discussionsupporting

confidence: 52%

Pharmacological characterization of anaphylaxis-like shock responses induced in mice by mannan and lipopolysaccharide

Funayama¹,

Huang²,

Sato³

et al. 2009

International Immunopharmacology

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Section: Discussionsupporting

confidence: 52%

Pharmacological characterization of anaphylaxis-like shock responses induced in mice by mannan and lipopolysaccharide

Funayama¹,

Huang²,

Sato³

et al. 2009

International Immunopharmacology

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“…However, we recently observed that platelets are protective in Fas-mediated hepatitis, when the hepatitis is local or not severe [21]. A very interesting point to note is that although LPS induces HPA, as described above, LPSpretreatment has been shown to protect mice against the hepatitis induced by either ConA or GalN + LPS [21][22][23][24][25]. As yet, the precise mechanisms underlying this protection remain unclear.…”

Section: Accepted M Manuscriptmentioning

confidence: 89%

“…Platelets were counted as described previously [21], and HPA was assessed by a method involving the use of 5HT as a marker for platelets [21,29,30].…”

Section: Platelet Count and Estimation Of Hpamentioning

confidence: 99%

Roles of platelets and macrophages in the protective effects of lipopolysaccharide against concanavalin A-induced murine hepatitis

Yu¹,

Otsuka²,

Yamaguchi³

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Platelets are reportedly causal in hepatitis. We previously showed that in mice, lipopolysaccharide (LPS) induces a reversible and macrophage-dependent hepatic platelet accumulation (HPA), including translocation of platelets into Disse spaces and their entry into hepatocytes. Concanavalin A (ConA), which induces hepatitis in mice via both T cells and macrophages, also induces HPA. Here, we examined the relationship between HPA and ConA-hepatitis. ConA-hepatitis and HPA were evaluated by serum transaminases, hepatic 5-hydroxytryptamine, and/or electron microscopy. Unlike LPS-induced HPA, ConA-induced HPA was only moderately dependent on phagocytic macrophages. Against expectations, platelet-depletion significantly exacerbated ConA-hepatitis, and anti-P-selectin antibody and P-selectin receptor blockade reduced both ConA-induced HPA and hepatitis. Prior induction of HPA by pretreatment with low-dose LPS powerfully reduced ConA-hepatitis. Such protection by LPS-pretreatment was not effective in mice depleted of phagocytic macrophages. In platelet-depleted mice, LPS-pretreatment severely exacerbated ConA-hepatitis. In mice depleted of both macrophages and platelets, neither ConA nor LPS-pretreatment+ConA induced hepatitis. In mice deficient in IL-1α and IL-1β (but not in TNFα), ConA-induced hepatitis was mild, and a protective effect of LPS was not detected. These results suggest that (i) there are causal and protective types of HPA, (ii) the causal type involves hepatic aggregation of platelets, which may be induced by platelet stimulants leaked from injured hepatocytes, (iii) the protective type is inducible by administration of prior low-dose LPS in a manner dependent on phagocytic (or F4/80-positive) macrophages, and (iv) IL-1 is involved in both the causal and protective types.

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“…However platelets are also a rich source of CD154 [22] and within seconds of activation CD154 is translocated to the platelet surface then cleaved to produce soluble CD154. Platelets have been implicated in preservation injury during liver transplantation and in other conditions including immune mediated damage in hepatitis although the mechanisms of the effect are poorly understood [44], [45], [46]. We now show that activated platelets secrete functional CD154 that is capable of inducing ROS accumulation in human hepatocytes during H-R leading to hepatocyte apoptosis.…”

Section: Discussionmentioning

confidence: 77%

Activation of CD40 with Platelet Derived CD154 Promotes Reactive Oxygen Species Dependent Death of Human Hepatocytes during Hypoxia and Reoxygenation

et al. 2012

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BackgroundHypoxia and hypoxia-reoxygenation (H-R) are pathogenic factors in many liver diseases that lead to hepatocyte death as a result of reactive oxygen species (ROS) accumulation. The tumor necrosis factor super-family member CD154 can also induce hepatocyte apoptosis via activation of its receptor CD40 and induction of autocrine/paracrine Fas Ligand/CD178 but the relationship between CD40 activation, ROS generation and apoptosis is poorly understood. We hypothesised that CD40 activation and ROS accumulation act synergistically to drive human hepatocyte apoptosis.MethodsHuman hepatocytes were isolated from liver tissue and exposed to an in vitro model of hypoxia and H-R in the presence or absence of CD154 and/or various inhibitors. Hepatocyte ROS production, apoptosis and necrosis were determined by labelling cells with 2′,7′-dichlorofluorescin, Annexin-V and 7-AAD respectively in a three-colour reporter flow cytometry assay.ResultsExposure of human hepatocytes to recombinant CD154 or platelet-derived soluble CD154 augments ROS accumulation during H-R resulting in NADPH oxidase-dependent apoptosis and necrosis. The inhibition of c-Jun N-terminal Kinase and p38 attenuated CD154-mediated apoptosis but not necrosis.ConclusionsCD154-mediated apoptosis of hepatocytes involves ROS generation that is amplified during hypoxia-reoxygenation. This finding provides a molecular mechanism to explain the role of platelets in hepatocyte death during ischemia-reperfusion injury.

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Hepatic platelet accumulation in Fas-mediated hepatitis in mice

Cited by 6 publications

References 38 publications

Pharmacological characterization of anaphylaxis-like shock responses induced in mice by mannan and lipopolysaccharide

Pharmacological characterization of anaphylaxis-like shock responses induced in mice by mannan and lipopolysaccharide

Roles of platelets and macrophages in the protective effects of lipopolysaccharide against concanavalin A-induced murine hepatitis

Activation of CD40 with Platelet Derived CD154 Promotes Reactive Oxygen Species Dependent Death of Human Hepatocytes during Hypoxia and Reoxygenation

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