The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model.

Abstract:

:Pulmonary arterial hypertension (PAH) is suspected to be a strong mortality determinant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimentally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, intermedilysin (ILY), exclusively lyses the erythrocytes of transgenically expressing human CD59 mice (ThCD59(RBC)), thereby inducing ILY-dose-dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailability and massive platelet activation/aggregation leading to the formation of massive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Therapeutic interventions enhancing NO bioactivity or inhibiting platelet activation prevented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pressure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and prevention of hemolysis-associated (fatal) PAH.

journal_name

Blood

journal_title

Blood

authors

Hu W,Jin R,Zhang J,You T,Peng Z,Ge X,Bronson RT,Halperin JA,Loscalzo J,Qin X

doi

10.1182/blood-2010-01-267112

subject

Has Abstract

pub_date

2010-09-02 00:00:00

pages

1613-22

issue

9

eissn

0006-4971

issn

1528-0020

pii

blood-2010-01-267112

journal_volume

116

pub_type

杂志文章

相关文献

BLOOD文献大全
  • The t(15;17) breakpoint in acute promyelocytic leukemia cluster within two different sites of the myl gene: targets for the detection of minimal residual disease by the polymerase chain reaction.

    abstract::The retinoic acid receptor alpha (RAR alpha) and the myl gene are involved in the translocation breakpoint t(15;17)(q22;q21) in acute promyelocytic leukemia (APL). The majority of the breakpoint sites have been mapped within the second intron of the RAR alpha gene; however, the breakpoint sites on the myl gene are var...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Chang KS,Lu JF,Wang G,Trujillo JM,Estey E,Cork A,Chu DT,Freireich EJ,Stass SA

    更新日期:1992-02-01 00:00:00

  • Platelet-delivered ADAMTS13 inhibits arterial thrombosis and prevents thrombotic thrombocytopenic purpura in murine models.

    abstract::ADAMTS13 metalloprotease cleaves von Willebrand factor (VWF), thereby inhibiting platelet aggregation and arterial thrombosis. An inability to cleave ultralarge VWF resulting from hereditary or acquired deficiency of plasma ADAMTS13 activity leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (T...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-07-587139

    authors: Pickens B,Mao Y,Li D,Siegel DL,Poncz M,Cines DB,Zheng XL

    更新日期:2015-05-21 00:00:00

  • Human erythropoietin gene therapy for patients with chronic renal failure.

    abstract::Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical condition is anemia. Patients with anemia of chronic renal failure are treated with erythropoietin. The objective of this study was to develop a therapeutic platform ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2004-11-4174

    authors: Lippin Y,Dranitzki-Elhalel M,Brill-Almon E,Mei-Zahav C,Mizrachi S,Liberman Y,Iaina A,Kaplan E,Podjarny E,Zeira E,Harati M,Casadevall N,Shani N,Galun E

    更新日期:2005-10-01 00:00:00

  • Interleukin-24 inhibits the plasma cell differentiation program in human germinal center B cells.

    abstract::Complex molecular mechanisms control B-cell fate to become a memory or a plasma cell. Interleukin-24 (IL-24) is a class II family cytokine of poorly understood immune function that regulates the cell cycle. We previously observed that IL-24 is strongly expressed in leukemic memory-type B cells. Here we show that IL-24...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2009-05-220251

    authors: Maarof G,Bouchet-Delbos L,Gary-Gouy H,Durand-Gasselin I,Krzysiek R,Dalloul A

    更新日期:2010-03-04 00:00:00

  • Parallel tubular arrays in severe combined immunodeficiency disease: an ultrastructural study of peripheral blood lymphocytes.

    abstract::The ultrastructure of the lymphocytes from three children with severe combined immunodeficiency disease (SCID) is described. Parallel tubular arrays (PTA) were found in a large percentage of circulating lymphocytes (53%, 41%, and 13%) in three SCID patients when compared to age-matched controls. The size of these incl...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Payne CM,Jones JF,Sieber OF Jr,Fulginiti VA

    更新日期:1977-07-01 00:00:00

  • BuMPing iron with modified heparins.

    abstract::In this issue of Blood, Poli et al demonstrate that heparin analogs engineered to minimize their anticoagulant properties can potently downregulate hepcidin production in vitro and in vivo, and may potentially be used to treat the anemia of inflammation. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2014-01-549519

    authors: Babitt JL,Lin HY

    更新日期:2014-03-06 00:00:00

  • Structural requirements for the activation of human factor VIII by thrombin.

    abstract::The coagulation factors V (FV) and VIII (FVIII) are important at sites of vascular injury for the amplification of the clotting cascade. Natural variants of these factors frequently lead to severe bleeding disorders. To understand the mechanisms of activation of FVIII by thrombin, we used a bank of mutant thrombins to...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-03-0843

    authors: Myles T,Yun TH,Leung LL

    更新日期:2002-10-15 00:00:00

  • Comparison of intravenous bolus injection or continuous infusion of recombinant single chain urokinase-type plasminogen activator (saruplase) for thrombolysis. A canine model of combined coronary arterial and femoral venous thrombosis.

    abstract::The thrombolytic efficacy of recombinant unglycosylated full length single chain urokinase-type plasminogen activator (rscu-PA, saruplase), applied either as single intravenous bolus or as a continuous infusion over 60 minutes, was studied in 5 randomized blinded groups of 5 dogs with combined copper coil induced coro...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Rapold HJ,Wu ZM,Stassen T,Van de Werf F,Collen D

    更新日期:1990-10-15 00:00:00

  • HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients.

    abstract::Human herpesvirus 6 (HHV-6) is detected in the plasma of approximately 40% of patients undergoing hematopoietic cell transplantation (HCT) and sporadically causes encephalitis in this population. The effect of HHV-6 reactivation on central nervous system function has not been fully characterized. This prospective stud...

    journal_title:Blood

    pub_type: 临床试验,杂志文章

    doi:10.1182/blood-2010-10-316083

    authors: Zerr DM,Fann JR,Breiger D,Boeckh M,Adler AL,Xie H,Delaney C,Huang ML,Corey L,Leisenring WM

    更新日期:2011-05-12 00:00:00

  • Plasmic degradation of fibrin rapidly decreases platelet adhesion and spreading.

    abstract::Plasmin cleaves fibrin at or near sites involved in platelet recognition and may modulate platelet adhesion and spreading. Using an in vitro system, we have characterized the effects of limited plasmic degradation of polymerized fibrin on platelet adhesion and spreading. As shown by scanning electron microscopy, expos...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hamaguchi M,Bunce LA,Sporn LA,Francis CW

    更新日期:1994-08-15 00:00:00

  • Longer in vivo survival of CD59- and decay-accelerating factor-almost normal positive and partly positive erythrocytes in paroxysmal nocturnal hemoglobinuria as compared with negative erythrocytes: a demonstration by differential centrifugation and flow c

    abstract::Three populations of erythrocytes have been shown by flow cytometric analysis on complement regulatory proteins: CD59 and decay-accelerating factor (DAF) on erythrocytes in paroxysmal nocturnal hemoglobinuria (PNH). CD59 and DAF in PNH may be completely deficient in CD59- and DAF-negative erythrocytes, they may be dec...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Fujioka S,Yamada T

    更新日期:1992-04-01 00:00:00

  • Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective.

    abstract::We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Enright H,Davies SM,DeFor T,Shu X,Weisdorf D,Miller W,Ramsay NK,Arthur D,Verfaillie C,Miller J,Kersey J,McGlave P

    更新日期:1996-07-15 00:00:00

  • The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia.

    abstract::Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer ty...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2016-05-714493

    authors: Li H,Mar BG,Zhang H,Puram RV,Vazquez F,Weir BA,Hahn WC,Ebert B,Pellman D

    更新日期:2017-01-26 00:00:00

  • Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3.

    abstract::Activation of p38 MAP kinase (p38) as well as JNK/SAPK has been described as being induced by a variety of environmental stresses such as osmotic shock, ultraviolet radiation, and heat shock, or the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 (IL-1). We found that the hematopoietic cytokine...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Nagata Y,Moriguchi T,Nishida E,Todokoro K

    更新日期:1997-08-01 00:00:00

  • Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation.

    abstract::Mitochondrial clearance is a well recognized but poorly understood biologic process, and reticulocytes, which undergo programmed mitochondrial clearance, provide a useful model to study this phenomenon. At the ultrastructural level, mitochondrial clearance resembles an autophagy-related process; however, the role of a...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2008-04-151639

    authors: Zhang J,Randall MS,Loyd MR,Dorsey FC,Kundu M,Cleveland JL,Ney PA

    更新日期:2009-07-02 00:00:00

  • CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors.

    abstract::Immunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment-free remission (TFR). We investigated effector and suppressor immune responses in CML patients at diagnosis (n = 21), on TKI (im...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2016-10-745992

    authors: Hughes A,Clarson J,Tang C,Vidovic L,White DL,Hughes TP,Yong AS

    更新日期:2017-03-02 00:00:00

  • The molecular defect in hypotransferrinemic mice.

    abstract::Hypotransferrinemic (Trf(hpx/hpx)) mice have a severe deficiency in serum transferrin (Trf) as the result of a spontaneous mutation linked to the murine Trf locus. They are born alive, but before weaning, die from severe anemia if they are not treated with exogenous Trf or red blood cell transfusions. We have determin...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Trenor CC 3rd,Campagna DR,Sellers VM,Andrews NC,Fleming MD

    更新日期:2000-08-01 00:00:00

  • A unique precipitating autoantibody against plasma thromboplastin antecedent associated with multiple apparent plasma clotting factor deficiencies in a patient with systemic lupus erythematosus.

    abstract::A 42-yr-old woman with systemic lupus erythematosus without bleeding diathesis developed a prolonged activated partial thromboplastin time that was not corrected by normal plasma. An inhibitor that acted rapidly and inactivated 0.5 U/ml plasma thromboplastin antecedent (PTA, factor XI) at a 1:200 plasma dilution was d...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Poon MC,Saito H,Koopman WJ

    更新日期:1984-06-01 00:00:00

  • Crosstalk between RANKL and Fas signaling in dendritic cells controls immune tolerance.

    abstract::Although receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) signaling has been shown to prolong the survival of mature dendritic cells (DCs), the association of RANKL pathway with Fas-mediated apoptosis is obscure. Here, we found that bone marrow-derived DCs (BMDCs) from the Fas-deficient strain MRL/lpr m...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-11-059980

    authors: Izawa T,Ishimaru N,Moriyama K,Kohashi M,Arakaki R,Hayashi Y

    更新日期:2007-07-01 00:00:00

  • The role of calcium in lymphocyte proliferation. (An interpretive review).

    abstract::A small quantity of extracellular calcium is required for the stimulation of lymphocytes by mitogens such as plant lectins. Lectin binding to the lymphocyte surface and early postbinding events that eventually lead to DNA synthesis are calcium dependent. Mitogenic lectins such as PHA and Con-A rapidly increase the siz...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:

    authors: Lichtman AH,Segel GB,Lichtman MA

    更新日期:1983-03-01 00:00:00

  • FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL.

    abstract::NOTCH1 is mutated in 10% of chronic lymphocytic leukemia (CLL) patients and is associated with poor outcome. However, NOTCH1 activation is identified in approximately one-half of CLL cases even in the absence of NOTCH1 mutations. Hence, there appear to be additional factors responsible for the impairment of NOTCH1 deg...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2018-09-874529

    authors: Close V,Close W,Kugler SJ,Reichenzeller M,Yosifov DY,Bloehdorn J,Pan L,Tausch E,Westhoff MA,Döhner H,Stilgenbauer S,Oswald F,Mertens D

    更新日期:2019-02-21 00:00:00

  • Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.

    abstract::CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2012-03-415448

    authors: Maude SL,Tasian SK,Vincent T,Hall JW,Sheen C,Roberts KG,Seif AE,Barrett DM,Chen IM,Collins JR,Mullighan CG,Hunger SP,Harvey RC,Willman CL,Fridman JS,Loh ML,Grupp SA,Teachey DT

    更新日期:2012-10-25 00:00:00

  • The biology and clinical impact of genetic lesions in myeloid malignancies.

    abstract::A longstanding endeavor to define the genetic lesions that drive myeloid malignances has stimulated a period of remarkable discovery. Enabled by technological advances that have sharply decreased the cost of DNA sequencing, the full compendium of common, recurrent somatic mutations in the coding genome of myeloid mali...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2013-06-460295

    authors: Lindsley RC,Ebert BL

    更新日期:2013-11-28 00:00:00

  • Perforin is a critical physiologic regulator of T-cell activation.

    abstract::Individuals with impaired perforin-dependent cytotoxic function (Ctx(-)) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). It has been hypothesized that immune hyperactivation during HLH is caused by heightened infection, defective apoptosis/responsiveness of Ctx(-) lymphocytes, or...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-12-324533

    authors: Lykens JE,Terrell CE,Zoller EE,Risma K,Jordan MB

    更新日期:2011-07-21 00:00:00

  • Association of tissue factor pathway inhibitor with human umbilical vein endothelial cells.

    abstract::Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor of the extrinsic coagulation system, synthesized in endothelial cells, which has recently been shown to play an important role in the regulation of activated coagulation factors at the endothelial cell surface. In the present study we investigated t...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hansen JB,Olsen R,Webster P

    更新日期:1997-11-01 00:00:00

  • Definitive but not primitive hematopoiesis is impaired in jumonji mutant mice.

    abstract::A novel gene, jumonji was identified by a mouse gene trap strategy. The jumonji gene encodes a protein containing a putative DNA binding domain. The mice homozygous for jumonji gene with a BALB/cA genetic background show hypoplasia of the fetal liver and embryonic lethality, suggesting impaired hematopoiesis. In the p...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Kitajima K,Kojima M,Nakajima K,Kondo S,Hara T,Miyajima A,Takeuchi T

    更新日期:1999-01-01 00:00:00

  • Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice.

    abstract::Here we report that a new nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse line harboring a complete null mutation of the common cytokine receptor gamma chain (NOD/SCID/interleukin 2 receptor [IL2r] gamma(null)) efficiently supports development of functional human hemato-lymphopoiesis. Purified human...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-02-0516

    authors: Ishikawa F,Yasukawa M,Lyons B,Yoshida S,Miyamoto T,Yoshimoto G,Watanabe T,Akashi K,Shultz LD,Harada M

    更新日期:2005-09-01 00:00:00

  • Soluble CD4, soluble CD8, soluble CD25, lymphopoieitic recovery, and endogenous cytokines after high-dose chemotherapy and blood stem cell transplantation.

    abstract::Mononuclear cell preparations from peripheral blood after mobilization with hematopoietic growth factors have been shown to induce accelerated neutrophil and platelet recovery as compared with that induced by autologous bone marrow transplantation after myeloablative chemotherapy. Because these mononuclear cell produc...

    journal_title:Blood

    pub_type: 临床试验,杂志文章

    doi:

    authors: Ho AD,Maruyama M,Maghazachi A,Mason JR,Glück S,Corringham RE

    更新日期:1994-11-15 00:00:00

  • C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia.

    abstract::Immune-mediated platelet destruction is most frequently caused by allo- or autoantibodies via Fcγ receptor-dependent phagocytosis. Disease severity can be predicted neither by antibody isotype nor by titer, indicating that other factors play a role. Here we show that the acute phase protein C-reactive protein (CRP), a...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-05-579110

    authors: Kapur R,Heitink-Pollé KM,Porcelijn L,Bentlage AE,Bruin MC,Visser R,Roos D,Schasfoort RB,de Haas M,van der Schoot CE,Vidarsson G

    更新日期:2015-03-12 00:00:00

  • Adenovirus-mediated cytotoxicity of chronic lymphocytic leukemia cells.

    abstract::We have studied adenovirus-mediated cytotoxicity after infection of malignant cells obtained from patients with chronic lymphocytic leukemia (CLL). Our studies indicate that adenoviruses can infect primary CLL cells and that infection of CLL cells with a replication-competent strain of human adenovirus 5 (Ad5dl309) re...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Medina DJ,Sheay W,Goodell L,Kidd P,White E,Rabson AB,Strair RK

    更新日期:1999-11-15 00:00:00