Role of fibrinolysis in tissue-factor-induced disseminated intravascular coagulation in rats - an effect of tranexamic acid

We clarified the role of fibrinolysis in tissue-factor (TF)-induced rat disseminated intravascular coagulation (DIC) using tranexamic acid (TA). TA suppressed the elevation in D-dimer levels normally observed following TF-induced DIC, and an increase in organ dysfunction was seen. Enhanced fibrinolysis plays an important role in preventing the development of organ failure in TF-induced DIC.     

Soluble c-kit receptor mobilizes hematopoietic stem cells to peripheral blood in mice

OBJECTIVE: The mechanisms of mobilization of hematopoietic stem cells (HSC) from bone marrow to peripheral blood (PB) by cytokines are poorly understood. One hypothesis is that cytokines disrupt cytoadhesive interactions of stem cells with bone marrow stroma. The soluble portion of c-kit (s-kit) binds stem cell factor (SCF) and can specifically block the ability of SCF to bind HSC. MATERIALS AND METHODS: To examine stem cell mobilization by s-kit, we prepared PB mononuclear cells from s-kit- or granulocyte colony-stimulating factor (G-CSF)-treated mice and assayed their colony-forming abilities and their long-term reconstituting abilities by transplantation into lethally irradiated Ly-5.2 congenic mice. RESULTS: We confirmed the published findings that human recombinant s-kit can block SCF-stimulated hematopoietic colony growing. We then found that s-kit could mobilize colony-forming cells from bone marrow to PB, and we found long-term reconstitution cells in the PB from s-kit-treated mice. The majority of s-kit-mobilized stem cells were in the CD34(+) cell population. We also tested the additive effect between G-CSF and s-kit. The mean percentages of donor cells in the mice transplanted with Lin(-) cells from the G-CSF-treated mice and the G-CSF/s-kit-treated mice were 44.6% and 64.8%, respectively (p=0.028). CONCLUSIONS: These findings demonstrate that stem cells with long-term engraftment capabilities can be mobilized by s-kit, and that s-kit combined with G-CSF treatment leads to significant enhancement of engraftment efficiency, suggesting mobilization via disruption between c-kit and SCF as the mechanism.     

Hepatic veno-occlusive disease after tranexamic acid administration in patients undergoing allogeneic hematopoietic stem cell transplantation

Tranexamic acid is one of the widely used antifibrinolytic agents. In spite of its effective inhibitory activity against plasminogen, thromboembolic adverse events caused by tranexamic acid are rare. We encountered three recipients of allogeneic hematopoietic stem cell transplantation (HSCT) who developed hepatic veno-occlusive disease (VOD) shortly after the administration of tranexamic acid. Hepatic VOD was resolved completely in all patients with the discontinuation of the drug, and with supportive measures with or without intravenous tissue plasminogen activator administration. These findings suggest that administration of tranexamic acid could be one of the possible risk factors for developing hepatic VOD in HSCT recipients.     

Successful cyclosporine treatment for thrombocytopenia after salvage therapy with arsenic trioxide therapy followed by autologous hematopoietic stem cell transplantation in acute promyelocytic leukemia

A 55-year-old man with acute promyelocytic leukemia in the first relapse was treated with arsenic trioxide as salvage therapy. After obtaining molecular remission, he underwent autologous peripheral blood stem cell transplantation (PBSCT) with busulfan and melphalan conditioning. The transplant dose of CD 34-positive cells was sufficient, and engraftment was prompt. Platelet count increased to 320 x 10(9)/1 on day 21; however, it rapidly decreased to 27 x 10(9)/l on day 37. Despite treatment with corticosteroid, the platelet count decreased to 6 x 10(9)/l on day 55. About one month after cyclosporine administration, thrombocytopenia gradually improved. This clinical course suggests immune-mediated thrombocytopenia following autologous PBSCT.     

Hyperexpression of inducible costimulator on lamina propria mononuclear cells in rat dextran sulfate sodium colitis

BACKGROUND AND AIMS: The authors have previously shown that a third member of the CD28 family, inducible costimulator (ICOS), was increased in the inflamed intestinal mucosa of murine experimental colitis, and that the blockade of ICOS ameliorated the development of colitis. However, the role of ICOS in rat intestinal inflammation and its expression profile remains unclear. In the present study, the authors investigated the involvement of ICOS in the development of rat dextran sulfate sodium (DSS)-induced colitis, and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in colitis. METHODS: The authors first examined expression of ICOS protein in normal rat by immunohistochemistry and flow cytometry. Sprague-Dawley rats were fed 3.0% DSS. The expression of ICOS on infiltrating lamina propria mononuclear cells and splenocytes were examined. The DSS-fed rats were then administered anti-ICOS mAb to test its effect on the development of colitis. RESULTS: Unlike mice and human, ICOS was expressed on a part of CD4+ T-cells from the thymus, spleen, mesenteric lymph nodes and lamina propria. Levels of ICOS on CD4+ T-cells from the spleen and colonic lamina propria were significantly upregulated after Concanavalin A (Con A) stimulation. In addition, ICOS was also upregulated on CD4+ T-cells from DSS-fed rats compared with those from non DSS-fed rats. However, anti-ICOS mAb did not ameliorate the development of both acute and chronic DSS colitis. CONCLUSION: These results suggest that the different expression of ICOS in rats plays a distinct role in rat intestinal inflammation.     

Distinct ontogenic and regional expressions of newly identified Cajal-Retzius cell-specific genes during neocorticogenesis

Cajal-Retzius (CR) cells are early-generated transient neurons and are important in the regulation of cortical neuronal migration and cortical laminar formation. Molecular entities characterizing the CR cell identity, however, remain largely elusive. We purified mouse cortical CR cells expressing GFP to homogeneity by fluorescence-activated cell sorting and examined a genome-wide expression profile of cortical CR cells at embryonic and postnatal periods. We identified 49 genes that exceeded hybridization signals by >10-fold in CR cells compared with non-CR cells at embryonic day 13.5, postnatal day 2, or both. Among these CR cell-specific genes, 25 genes, including the CR cell marker genes such as the reelin and calretinin genes, are selectively and highly expressed in both embryonic and postnatal CR cells. These genes, which encode generic properties of CR cell specificity, are eminently characterized as modulatory composites of voltage-dependent calcium channels and sets of functionally related cellular components involved in cell migration, adhesion, and neurite extension. Five genes are highly expressed in CR cells at the early embryonic period and are rapidly down-regulated thereafter. Furthermore, some of these genes have been shown to mark two distinctly different focal regions corresponding to the CR cell origins. At the late prenatal and postnatal periods, 19 genes are selectively up-regulated in CR cells. These genes include functional molecules implicated in synaptic transmission and modulation. CR cells thus strikingly change their cellular phenotypes during cortical development and play a pivotal role in both corticogenesis and cortical circuit maturation.     

A Japanese family with ferroportin disease caused by a novel mutation of SLC40A1 gene: hyperferritinemia associated with a relatively low transferrin saturation of iron

Ferroportin disease, autosomal-dominant reticuloendothelial iron overload, may be more prevalent than hemochromatosis in Japan. Hyperferritinemia of 822 ng/ml with 24.8% transferrin saturation of iron was incidentally noted in a 43-year-old man. His iron overload was selective in Kupffer cells of the liver. Subsequently, his father was found to have asymptomatic hyperferritinemia of 2,283 ng/ml with 62.1% saturation. These affected subjects were heterozygous for 1467A>C (R489S) in SLC40A1, and without other mutations of the hemochromatosis genes. Here, we report a Japanese family with ferroportin disease, characterized by hyperferritinemia with relatively low transferrin saturations of iron.     

Adiponectin inhibits endothelial synthesis of interleukin-8

Adiponectin is an antiatherogenic adipokine that inhibits inflammation by mechanisms that are not completely understood. We explored the effect of adiponectin on endothelial synthesis of interleukin-8 (IL-8), a pro-inflammatory chemokine that plays a role in atherogenesis. Adiponectin decreased the secretion of IL-8 from human aortic endothelial cells (HAEC) stimulated with tumor necrosis factor-alpha (TNF-alpha). Adiponectin also inhibited IL-8 mRNA expression induced by TNF-alpha. Phosphorylation of IkappaB-alpha was decreased by adiponectin, but phosphorylation of ERK, SAPK/JNK, and p38MAPK were unaffected. Adiponectin increased intra-cellular cAMP levels in HAEC in a dose-dependent manner; PKA activity was also increased. The inhibitory effect of adiponectin on TNF-alpha-induced IL-8 synthesis was inhibited by pretreatment with Rp-cAMP, a PKA inhibitor. These observations suggest that adiponectin inhibits IL-8 synthesis through inhibition of a PKA dependent NF-kappaB signaling pathway. We also showed that adiponectin enhances Akt phosphorylation. The inhibitory effect of adiponectin on TNF-alpha-induced IL-8 synthesis was abrogated in part by pretreatment with the PI3 kinase inhibitor LY294002 or by Akt siRNA transfection, suggesting that Akt activation might inhibit IL-8 synthesis induced by TNF-alpha. We conclude that inhibition of NF-kappaB and activation of Akt phosphorylation may mediate adiponectin inhibition of atherosclerosis.     

Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice

It has been shown that angiogenesis plays an important role not only in tumor growth, but also in early carcinogenesis. The expression of a potent angiogenic factor, vascular endothelial growth factor (VEGF), increased during the early stage of carcinogenesis. In this study, the effects of the neutralizing monoclonal antibodies R1 mAb and R2 mAb of the VEGF receptors Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), respectively, on murine hepatocarcinogenesis induced by diethylnitrosamine (DEN) were examined. The effects of R1 mAb and R2 mAb on spontaneous lung metastasis from hepatocellular carcinoma (HCC) were also investigated. VEGF expression and neovascularization in the tumor increased stepwise during hepatocarcinogenesis. Treatment with both R1 mAb and R2 mAb markedly inhibited the development of HCC and adenoma in the liver. The inhibitory effect of R2 mAb was more potent than that of R1 mAb, and the combination treatment with both mAbs almost completely attenuated hepatocarcinogenesis. Both R1 mAb and R2 mAb treatment significantly suppressed the development of angiogenesis in HCC. The suppressive effects against angiogenesis R1 mAb and R2 mAb were similar in magnitude to their inhibitory effects against hepatocarcinogenesis. Furthermore, spontaneous lung metastasis from HCC was also significantly suppressed by R1 mAb and R2 mAb treatment. In conclusion, these results suggest that VEGF and receptor interaction plays an important role in hepatocarcinogenesis and in spontaneous lung metastasis from HCC.