scholarly journals Urocortins and Cholecystokinin-8 Act Synergistically to Increase Satiation in Lean But Not Obese Mice: Involvement of Corticotropin-Releasing Factor Receptor-2 Pathway

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6115-6123 ◽  
Author(s):  
G. Gourcerol ◽  
L. Wang ◽  
Y. H. Wang ◽  
M. Million ◽  
Y. Taché
Keyword(s):  
Corticotropin Releasing Factor ◽  
Vehicle Group ◽  
Afferent Activity ◽  
Wild Type ◽  
Rat Stomach ◽  
Urocortin 1 ◽  
Crf2 Receptor ◽  
Vagal Afferent ◽  
Deficient Mice

Interactions between gastrointestinal signals are a part of integrated systems regulating food intake (FI). We investigated whether cholecystokinin (CCK)-8 and urocortin systems potentiate each other to inhibit FI and gastric emptying (GE) in fasted mice. Urocortin 1 and urocortin 2 (1 μg/kg) were injected ip alone or with CCK (3 μg/kg) in lean, diet-induced obese (DIO) or corticotropin-releasing factor receptor-2 (CRF2)-deficient mice. Gastric vagal afferent activity was recorded from a rat stomach-vagus in vitro preparation. When injected separately, urocortin 1, urocortin 2, or CCK did not modify the 4-h cumulative FI in lean mice. However, CCK plus urocortin 1 or CCK plus urocortin 2 decreased significantly the 4-h FI by 39 and 27%, respectively, compared with the vehicle + vehicle group in lean mice but not in DIO mice. Likewise, CCK-urocortin-1 delayed GE in lean but not DIO mice, whereas either peptide injected alone at the same dose had no effect. CCK-urocortin 2 suppression of FI was observed in wild-type but not CRF2-deficient mice. Gastric vagal afferent activity was increased by intragastric artery injection of urocortin 2 after CCK at a subthreshold dose, and the response was reversed by devazepide. These data establish a peripheral synergistic interaction between CCK and urocortin 1 or urocortin 2 to suppress FI and GE through CRF2 receptor in lean mice that may involve CCK modulation of gastric vagal afferent responsiveness to urocortin 2. Such synergy is lost in DIO mice, suggesting a resistance to the satiety signaling that may contribute to maintain obesity.

scholarly journals Toll-Like Receptor 2 Controls the Gamma Interferon Response to Francisella tularensis by Mouse Liver Lymphocytes

2007 ◽  
Vol 75 (11) ◽  
pp. 5338-5345 ◽  
Author(s):  
Kee-Jong Hong ◽  
Jason R. Wickstrum ◽  
Hung-Wen Yeh ◽  
Michael J. Parmely
Keyword(s):  
Francisella Tularensis ◽  
Cell Types ◽  
Gamma Interferon ◽  
Interferon Response ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT The production of gamma interferon (IFN-γ) is a key step in the protective innate immune response to Francisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primary F. tularensis infections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN-γ expression. The present study was undertaken to determine whether or not macrophages (Mφ) or dendritic cells (DC) provide coactivating signals for the liver IFN-γ response in vitro, whether IL-12 mediates these effects, and whether Toll-like receptor (TLR) signaling is essential to induce this costimulatory activity. Both bone marrow-derived Mφ and DC significantly augmented the IFN-γ response of F. tularensis-challenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response to F. tularensis challenge, only DC secreted large quantities of IL-12p70. DC from both IL-12p35-deficient and TLR2-deficient mice failed to produce IL-12p70 and did not costimulate liver lymphocytes for IFN-γ production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-γ at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-γ responses to F. tularensis by regulating DC IL-12 production. While Mφ also coinduced hepatic IFN-γ production in response to F. tularensis, they did so in a fashion less dependent on TLR2.

scholarly journals An in vivo inflammatory loop potentiates KRAS blockade

2019 ◽  
Author(s):  
Kristina A.M. Arendt ◽  
Giannoula Ntaliarda ◽  
Vasileios Armenis ◽  
Danai Kati ◽  
Christin Henning ◽  
...  
Keyword(s):  
Interleukin 1Β ◽  
Wild Type ◽  
Poor Survival ◽  
Murine Bone Marrow ◽  
Chemokine Ligand ◽  
Isoprenylcysteine Carboxylmethyltransferase ◽  
Chemokine Ligand 2 ◽  
Deficient Mice

ABSTRACTKRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1β blockade might be specific for KRAS-mutant cancers.

scholarly journals Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

2019 ◽  
Vol 20 (20) ◽  
pp. 4989 ◽  
Author(s):  
Yoshinori Tanino ◽  
Xintao Wang ◽  
Takefumi Nikaido ◽  
Kenichi Misa ◽  
Yuki Sato ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Heparan Sulfate ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Lung Fibroblasts ◽  
Fibrosis Score ◽  
Wild Type ◽  
Deficient Mice

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis

2001 ◽  
Vol 280 (2) ◽  
pp. G291-G297 ◽  
Author(s):  
Cameron W. Lush ◽  
Gediminas Cepinskas ◽  
William J. Sibbald ◽  
Peter R. Kvietys
Keyword(s):  
Leukocyte Adhesion ◽  
Cecal Ligation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Endothelial Adhesion Molecule ◽  
Acute Peritonitis ◽  
Leukocyte Accumulation ◽  
Deficient Mice

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)−/− mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS−/− and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS−/− mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS−/− mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS−/− mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS−/− mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.

scholarly journals A Role for Mac-1 (CDIIb/CD18) in Immune Complex–stimulated Neutrophil Function In Vivo: Mac-1 Deficiency Abrogates Sustained Fcγ Receptor–dependent Neutrophil Adhesion and Complement-dependent Proteinuria in Acute Glomerulonephritis

1997 ◽  
Vol 186 (11) ◽  
pp. 1853-1863 ◽  
Author(s):  
Tao Tang ◽  
Alexander Rosenkranz ◽  
Karel J.M. Assmann ◽  
Michael J. Goodman ◽  
Jose-Carlos Gutierrez-Ramos ◽  
...  
Keyword(s):  
Immune Complex ◽  
Mutant Mice ◽  
Polymorphonuclear Neutrophil ◽  
Complement C3 ◽  
Acute Glomerulonephritis ◽  
Wild Type ◽  
Filamentous Actin ◽  
Deficient Mice

Mac-1 (αmβ2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcγ receptors to facilitate immune complex (IC)–stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1–FcγR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti–glomerular basement membrane (GBM) nephritis in wild-type and Mac-1–deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1– deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1–null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5–12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1–FcγR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1–FcγR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3–deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1–null mice.

scholarly journals Interleukin 10- and Fcγ Receptor-Deficient Mice Resolve Leishmania mexicana Lesions

2005 ◽  
Vol 73 (4) ◽  
pp. 2101-2108 ◽  
Author(s):  
Laurence U. Buxbaum ◽  
Phillip Scott
Keyword(s):  
Chronic Disease ◽  
Interleukin 10 ◽  
Delayed Type Hypersensitivity ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Enhanced Resistance ◽  
Lymph Node Cells ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Infection of C57BL/6 (B6) mice with Leishmania mexicana is associated with a minimal immune response and chronic disease. Here we show that B6 interleukin 10−/− (IL-10−/−) mice resolve their lesions and exhibit increased gamma interferon (IFN-γ), nitric oxide production, and delayed-type hypersensitivity. This enhanced resistance was dependent upon IL-12p40, since treatment of L. mexicana-infected IL-10−/− mice with anti-IL-12p40 monoclonal antibody abrogated healing. Antibody-opsonized L. mexicana induced IL-10 production by B6 macrophages in vitro, implicating antibody binding to Fc receptors as a mechanism involved in IL-10 production in this infection. Furthermore, B6 FcRγ−/− mice resolve L. mexicana lesions, and lymph node cells from these mice produced less IL-10 and more IFN-γ than cells from infected wild-type mice. These data demonstrate that removal of IL-10 or FcγR leads to resolution of L. mexicana disease and support a model in which ligation of FcγR by L. mexicana-bound immunoglobulin G promotes IL-10 production, leading to chronic disease.

scholarly journals Gastric Vagal Efferent Inhibition Evoked by Intravenous CRF Is Unrelated to Simultaneously Recorded Vagal Afferent Activity in Urethane-Anesthetized Rats

2007 ◽  
Vol 97 (4) ◽  
pp. 3004-3014 ◽  
Author(s):  
David W. Adelson ◽  
Hovsep P. Kosoyan ◽  
Yuhua Wang ◽  
Justin Z. Steinberg ◽  
Yvette Taché
Keyword(s):  
Impulse Activity ◽  
Simultaneous Recording ◽  
Corticotropin Releasing Factor ◽  
Inhibitory Influence ◽  
Afferent Activity ◽  
Nerve Branch ◽  
Gastric Tone ◽  
Gastric Distention ◽  
Anesthetized Rats ◽  
Vagal Afferent

Corticotropin-releasing factor (CRF) injected peripherally or released in response to stressful challenges to the organism reduces gastric tone and contractility, in part by vagal pathways. However, information on the changes in gastric vagal impulse activity evoked by peripheral CRF administration is entirely lacking. Using a novel “dual recording” method in urethane-anesthetized rats, vagal efferent (VE) and afferent (VA) impulse activities were recorded simultaneously from separate, fine bundles dissected from the ventral gastric vagus nerve branch innervating the glandular stomach. Activity records for 38 VA single units (SUs) and 33 VE SUs were sorted from multiunit records obtained from 13 preparations. Intravenous (iv) administration of saline had no effect on multiunit VE activity, whereas CRF (1 μg/kg, iv) immediately inhibited VE activity, reaching a nadir of 54 ± 8.0% of preinjection levels at 3.0 min postinjection. CRF (1 μg/kg, iv) inhibited 25/33 (75.8%) VE SUs and excited three of 33 (9.1%) VE SUs. In contrast to potent effects on VE activity, iv CRF did not alter multiunit VA activity. Single-unit analysis, however, revealed five of 38 (13.1%) VA SUs excited by iv CRF at widely varying latencies (suggesting an indirect mode of action) and one inhibited VA SU. VA SUs excited after iv CRF did not respond during gastric distention and vice versa. These experiments are the first to use simultaneous recording of gastric VA and VE units. The data demonstrate a predominantly inhibitory influence of iv CRF on VE outflow to the hindstomach, not driven by gastric vagovagal reflex activity.

Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo

2019 ◽  
Vol 12 (574) ◽  
pp. eaao7232 ◽  
Author(s):  
Katsuhiko Itoh ◽  
Gen Kondoh ◽  
Hitoshi Miyachi ◽  
Manabu Sugai ◽  
Yoshiyuki Kaneko ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Sperm Maturation ◽  
Sperm Cells ◽  
Chromatin Binding ◽  
Wild Type ◽  
Underlying Mechanisms ◽  
Deficient Mice ◽  
Protamine 2

The posttranslational modification of histones is crucial in spermatogenesis, as in other tissues; however, during spermiogenesis, histones are replaced with protamines, which are critical for the tight packaging of the DNA in sperm cells. Protamines are also posttranslationally modified by phosphorylation and dephosphorylation, which prompted our investigation of the underlying mechanisms and biological consequences of their regulation. On the basis of a screen that implicated the heat shock protein Hspa4l in spermatogenesis, we generated mice deficient in Hspa4l (Hspa4l-null mice), which showed male infertility and the malformation of sperm heads. These phenotypes are similar to those of Ppp1cc-deficient mice, and we found that the amount of a testis- and sperm-specific isoform of the Ppp1cc phosphatase (Ppp1cc2) in the chromatin-binding fraction was substantially less in Hspa4l-null spermatozoa than that in those of wild-type mice. We further showed that Ppp1cc2 was a substrate of the chaperones Hsc70 and Hsp70 and that Hspa4l enhanced the release of Ppp1cc2 from these complexes, enabling the freed Ppp1cc2 to localize to chromatin. Pull-down and in vitro phosphatase assays suggested the dephosphorylation of protamine 2 at serine 56 (Prm2 Ser56) by Ppp1cc2. To confirm the biological importance of Prm2 Ser56 dephosphorylation, we mutated Ser56 to alanine in Prm2 (Prm2 S56A). Introduction of this mutation to Hspa4l-null mice (Hspa4l−/−; Prm2S56A/S56A) restored the malformation of sperm heads and the infertility of Hspa4l−/− mice. The dephosphorylation signal to eliminate phosphate was crucial, and these results unveiled the mechanism and biological relevance of the dephosphorylation of Prm2 for sperm maturation in vivo.

PI3K/Akt/FOXO3a Pathway Contributes to Thrombopoietin-Induced Proliferation of Primary Megakaryocytes In Vitro and In Vivo Via Modulation of p27Kip1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 202-202
Author(s):  
Takafumi Nakao ◽  
Amy E Geddis ◽  
Norma E. Fox ◽  
Kenneth Kaushansky
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Cycle Progression ◽  
Wild Type ◽  
Cycle Progression ◽  
P27kip1 Expression ◽  
Cell Counts ◽  
Deficient Mice

Abstract Thrombopoietin (TPO), the primary regulator of megakaryocyte (MK) and platelet formation, modulates the activity of multiple signal transduction molecules, including those in the Jak/STAT, p42/p44 MAPK, and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. In the previous study, we reported that PI3K and Akt are necessary for TPO-induced cell cycle progression of primary MK progenitors. The absence of PI3K activity results in a block of transition from G1 to S phase in these cells (Geddis AE et al. JBC2001276:34473–34479). However, the molecular events secondary to the activation of PI3K/Akt responsible for MK proliferation remain unclear. In this study we show that FOXO3a and its downstream target p27Kip1 play an important role in TPO-induced proliferation of MK progenitors. TPO induces phosphorylation of Akt and FOXO3a in both UT-7/TPO, a megakaryocytic cell line, and primary murine MKs in a PI3K dependent fashion. Cell cycle progression of UT-7/TPO cells is blocked in G1 phase by inhibition of PI3K. We found that TPO down-modulates p27Kip1 expression at both the mRNA and protein levels in UT-7/TPO cells and primary MKs in a PI3K dependent fashion. UT-7/TPO stably expressing constitutively active Akt or a dominant-negative form of FOXO3a failed to induce p27Kip1 expression after TPO withdrawal. Induced expression of an active form of FOXO3a resulted in increased p27Kip1 expression in this cell line. In an attempt to assess whether FOXO3a has an effect of MK proliferation in vivo, we compared the number of MKs in Foxo3a-deficient mice and in wild type controls. Although peripheral blood cell counts of erythrocytes, neutrophils, monocytes and platelets were normal in the Foxo3a-deficient mice, total nucleated marrow cell count of Foxo3a-deficient mice were 60% increased compared with wild type controls. In addition, the increase of MKs was more profound than that of total nucleated marrow cells; CD41+ MKs from Foxo3a-deficient mice increased 2.1-fold, and mature MKs with 8N and greater ploidy increased 2.5-fold, compared with wild type controls. Taken together with the previous observation that p27Kip1-deficient mice also display increased numbers of MK progenitors, our findings strongly suggest that the effect of TPO on MK proliferation is mediated by PI3K/Akt-induced FOXO3a inactivation and subsequent p27Kip1 down-regulation in vitro and in vivo.

Monocyte-Derived Microparticles Improve Hemostasis in Factor VIIIDeficient Mice: Exploring the Role of PSGL-1/P-Selectin.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3386-3386
Author(s):  
Peter L. Gross ◽  
Nima Vaezzadeh ◽  
Lori Ivicic ◽  
Ran Ni ◽  
Bruno Esposito ◽  
...  
Keyword(s):  
Blood Loss ◽  
High Speed ◽  
Calcium Ionophore ◽  
Ionophore A23187 ◽  
Wild Type ◽  
Spontaneous Bleeding ◽  
Platelet Accumulation ◽  
Deficient Mice ◽  
Tail Clip

Abstract Introduction: Microparticles derived from leukocytes contribute to fibrin formation at thrombi in vivo and factor VIII-deficient (FVIII) mice treated with an agent that elevates their microparticles have decreased bleeding. A novel therapy for hemophilia patients with inhibitors is needed. We evaluated whether microparticles generated in vitro could improve hemostasis in FVIII mice. Methods: Mouse CD11b positive monocytes, isolated by MACS, or cultured monocytic cells (WEHI274.1) were treated with the calcium ionophore A23187. The resulting microparticles (isolated by differential centrifugation, and defined as CD18 positive events less than 1 μm diameter) or PIPES buffer were infused intravenously into FVIII-deficient mice (B6.129S4-F8tm1Kaz) or control wild type B6.129 mice prior to evaluation. The amount of platelets in laser-generated thrombi in cremaster muscle arterioles was evaluated using high-speed intravital fluorescence microscopy. The amount of hemoglobin shed from a 2 mm tail tip amputation measured blood loss. Results: Infusion of MPs at doses above 1000/g resulted in the death of wild type mice; FVIII-deficient mice tolerated MPs at doses up to 4000/g. Blood loss after tail clip in FVIII-deficient mice was 6-fold higher than blood loss from wild type mice. Blood loss after tail clip in FVIII-deficient mice was reduced to normal after the infusion of MPs at concentrations as low as 400/g. MPs, at 400/g, from CD11b positive cells isolated from wild type, FVIII-deficient mice or PSGL-1-deficient mice all similarly reduced blood loss after tail clip in FVIII-deficient mice. The biological half life of MP effect on tail-bleeding was 3 hours. Platelet accumulation in cremaster arteriolar thrombi was impaired in FVIII-deficient mice. Infusion of MPs at a concentration of 1000/g normalized platelet accumulation, but infusion of MPs at a lower concentration (400/g) did not. Conclusion: Abnormal hemostasis in FVIII-deficient mice can be temporarily reversed by the infusion of in vitro generated monocyte-derived MPs, including MPs derived from monocytes from FVIII-deficient or PSGL-1-deficient mice. The dose whereby MPs normalize FVIII-deficient mice is different between the hemostasis and thrombosis models. To explore whether P-selectin at injuries is required for the effect of MPs, we have generated by cross-breeding FVIII/P-selectin double deficient mice. These mice are born at expected mendelian frequency. Two of 20 male FVIII/P-selectin double deficient mice had spontaneous bleeding at 8 weeks of age, one in the thigh and one from the ear. FVIII/P-selectin double deficient mice also have prolonged tail bleeding times, which will serve as a model for testing the P-selectin targeting of microparticles.

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