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Marcus Maurer Werner Aberer Laurence Bouillet Teresa Caballero Vincent Fabien Gisèle Kanny Allen Kaplan Hilary Longhurst Andrea Zanichelli 《PloS one》2013,8(2)
Background
Attacks of hereditary angioedema (HAE) are unpredictable and, if affecting the upper airway, can be lethal. Icatibant is used for physician- or patient self-administered symptomatic treatment of HAE attacks in adults. Its mode of action includes disruption of the bradykinin pathway via blockade of the bradykinin B2 receptor. Early treatment is believed to shorten attack duration and prevent severe outcomes; however, evidence to support these benefits is lacking.Objective
To examine the impact of timing of icatibant administration on the duration and resolution of HAE type I and II attacks.Methods
The Icatibant Outcome Survey is an international, prospective, observational study for patients treated with icatibant. Data on timings and outcomes of icatibant treatment for HAE attacks were collected between July 2009–February 2012. A mixed-model of repeated measures was performed for 426 attacks in 136 HAE type I and II patients.Results
Attack duration was significantly shorter in patients treated <1 hour of attack onset compared with those treated ≥1 hour (6.1 hours versus 16.8 hours [p<0.001]). Similar significant effects were observed for <2 hours versus ≥2 hours (7.2 hours versus 20.2 hours [p<0.001]) and <5 hours versus ≥5 hours (8.0 hours versus 23.5 hours [p<0.001]). Treatment within 1 hour of attack onset also significantly reduced time to attack resolution (5.8 hours versus 8.8 hours [p<0.05]). Self-administrators were more likely to treat early and experience shorter attacks than those treated by a healthcare professional.Conclusion
Early blockade of the bradykinin B2 receptor with icatibant, particularly within the first hour of attack onset, significantly reduced attack duration and time to attack resolution. 相似文献3.
Both NS3 protein (1007-1657) and its protease moiety (NS3p, 1027-1207) were able to interact in vitro with C1 Inhibitor (C1Inh) to give a 95-kDa Mr C1Inh cleavage product similar to that obtained upon proteolysis by complement protease C1s. High-Mr reaction products were also detected after incubation of C1Inh with NS3 but not with NS3p; they correspond to ester-bonded complexes from their hydroxylamine lability. Similar reactivity of NS3 was observed upon incubation with alpha2-antiplasmin. Serpin cleavage was prevented by treatment of NS3 with synthetic serine protease inhibitors. This interaction between viral NS3 and host serpins suggests that NS3 is likely to be controlled by infected cell protease inhibitors. 相似文献
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Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death 下载免费PDF全文
Coultas L Bouillet P Stanley EG Brodnicki TC Adams JM Strasser A 《Molecular and cellular biology》2004,24(4):1570-1581
The BH3-only members of the Bcl-2 protein family are essential for initiation of programmed cell death and stress-induced apoptosis. We have determined the expression pattern in mice of the BH3-only protein Bik, also called Blk or Nbk, and examined its physiological function by gene targeting. We found that Bik is expressed widely in the hematopoietic compartment and in endothelial cells of the venous but not arterial lineages. Nevertheless, its loss did not increase the numbers of such cells in mice or protect hematopoietic cells in vitro from apoptosis induced by cytokine withdrawal or diverse other cytotoxic stimuli. Moreover, whereas loss of the BH3-only protein Bim rescued mice lacking the prosurvival protein Bcl-2 from fatal polycystic kidney disease and lymphopenia, loss of Bik did not. These results indicate that any function of Bik in programmed cell death and stress-induced apoptosis must overlap that of other BH3-only proteins. 相似文献
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Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis 总被引:41,自引:0,他引:41
Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis-dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX-mediated cytochrome c (cyt c) release. The gene products triggering this process remain unknown. Here, we report that BIM, a member of the BH3-only proapoptotic subfamily of the BCL-2 protein family, is one such molecule. NGF withdrawal induced expression of BIM(EL), an integral mitochondrial membrane protein that functions upstream of (or in parallel with) the BAX/BCL-2 and caspase checkpoints. Bim deletion conferred protection against developmental and induced neuronal apoptosis in both central and peripheral populations, but only transiently, suggesting that BIM--and perhaps other BH3-only proteins--serve partially redundant functions upstream of BAX-mediated cyt c release. 相似文献
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M A Debrincat I Pleines M Lebois R M Lane M L Holmes J Corbin C J Vandenberg W S Alexander A P Ng A Strasser P Bouillet M Sola-Visner B T Kile E C Josefsson 《Cell death & disease》2015,6(4):e1721
Navitoclax (ABT-263), an inhibitor of the pro-survival BCL-2 family proteins BCL-2, BCL-XL and BCL-W, has shown clinical efficacy in certain BCL-2-dependent haematological cancers, but causes dose-limiting thrombocytopaenia. The latter effect is caused by Navitoclax directly inducing the apoptotic death of platelets, which are dependent on BCL-XL for survival. Recently, ABT-199, a selective BCL-2 antagonist, was developed. It has shown promising anti-leukaemia activity in patients whilst sparing platelets, suggesting that the megakaryocyte lineage does not require BCL-2. In order to elucidate the role of BCL-2 in megakaryocyte and platelet survival, we generated mice with a lineage-specific deletion of Bcl2, alone or in combination with loss of Mcl1 or Bclx. Platelet production and platelet survival were analysed. Additionally, we made use of BH3 mimetics that selectively inhibit BCL-2 or BCL-XL. We show that the deletion of BCL-2, on its own or in concert with MCL-1, does not affect platelet production or platelet lifespan. Thrombocytopaenia in Bclx-deficient mice was not affected by additional genetic loss or pharmacological inhibition of BCL-2. Thus, BCL-2 is dispensable for thrombopoiesis and platelet survival in mice.Platelets are anucleate blood cells that play essential roles in haemostasis, wound healing and a range of other processes, including inflammation and immunity.1 They are produced by megakaryocytes, large polyploid cells that develop primarily in the bone marrow, spleen and foetal liver.2 Recent work has demonstrated that the survival of megakaryocytes and platelets is governed by the BCL-2 family proteins.3 Both cell types possess a classical BAK/BAX-mediated intrinsic apoptosis pathway that must be restrained in order for them to develop and survive.In platelets, BCL-XL is the critical pro-survival BCL-2 family member required to keep BAK and BAX in check. The first evidence of this came from Wagner et al.,4 who reported severe thrombocytopaenia in mice after MMTV-Cre-mediated deletion of Bclx in the haematopoietic system, skin and various secretory tissues. It has since been shown that megakaryocyte-restricted deletion of Bclx in mice reduces platelet lifespan from ~5 days to ~5 h, with a concomitant decrease in platelet counts to ~2% of wild-type levels.5, 6 Pharmacological inhibition of BCL-XL with the BH3 mimetics ABT-7377 or Navitoclax (ABT-263)8 (which both also inhibit BCL-2 and BCL-W) triggers BAK/BAX-mediated platelet apoptosis.9, 10, 11 As a result, these drugs cause dose-dependent thrombocytopaenia in mice, dogs and humans.9, 11, 12, 13, 14 Indeed, thrombocytopaenia is the dose-limiting toxicity for Navitoclax.12, 13, 14 This fact provided additional impetus for the development of agents that specifically target BCL-2, beginning with ABT-199,15 a BCL-2-selective antagonist currently in clinical trials for the treatment of a range of haematological malignancies including chronic lymphocytic leukaemia, non-Hodgkin''s lymphoma, follicular lymphoma, mantle cell lymphoma, multiple myeloma and acute myeloid leukaemia. ABT-199 has already shown very promising anti-tumour activity, with little to no impact on platelet counts.15, 16 These data suggest that BCL-2 is dispensable for the development and survival of platelets.In megakaryocytes, BCL-XL is also critical for survival. Although not absolutely required for their growth and maturation, BCL-XL is essential for megakaryocytes to proceed safely through pro-platelet formation and platelet shedding.5 In addition to BCL-XL, megakaryocytes also depend on the pro-survival activity of MCL-1. Conditional deletion of Mcl1 alone has no effect on this lineage. In contrast, combined megakaryocyte-specific loss of Bclx and Mcl1 results in the failure of megakaryopoiesis, systemic haemorrhage and embryonic lethality.5, 17, 18 These defects are rescued by deletion of Bak and Bax.18Consistent with the genetic studies, administration of ABT-737 to Mcl1Pf4Δ/Pf4Δ mice, which lack MCL-1 in megakaryocytes and platelets, induces acute, fulminant BAK/BAX-dependent megakaryocyte apoptosis. Given that, in addition to BCL-XL, ABT-737 also targets BCL-2,7 these data suggested that BCL-2 might also contribute to the development and survival of the megakaryocyte lineage. This is supported by recent studies demonstrating that neonatal human platelets contain increased levels of BCL-2 relative to adult counterparts,19 and that platelet lifespan is extended in transgenic mice expressing BCL-2 under the control of the pan-haematopoietic Vav promoter.20 In light of these observations, and intense ongoing activity surrounding the development of novel BH3 mimetics,21 we set out to elucidate the role of BCL-2 in megakaryocytes and platelets. Mice with a megakaryocyte-specific deletion of Bcl2, either alone or in combination with deletion of Mcl1 or Bclx, were generated. The effect of these mutations, and of BCL-2 or BCL-XL-selective BH3 mimetics, on the megakaryocyte lineage was assessed. 相似文献
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Hughes P Robati M Lu W Zhou J Strasser A Bouillet P 《Cell death and differentiation》2006,13(7):1123-1127
We have recently demonstrated that ablation of one or both alleles of the proapoptotic gene Bim prevents the polycystic kidney disease (PKD) that develops in mice deficient for the prosurvival protein Bcl-2. The aim of the present study was to investigate whether loss of Bim or Bcl-2 could influence the disease in the PKD1del34/del34 mutant mice, a model of autosomal dominant PKD. PKD1del34/del34 mice were intercrossed with Bim-deficient mice and Bcl-2+/- mice to generate double mutants. Loss of Bim does not prevent the development of PKD in PKD1del34/del34 mice. On the C57BL/6 genetic background, most older PKD1del34/+ mice do not develop PKD, but present with liver cysts. Surprisingly, loss of Bim completely prevented liver cysts formation in PKD1del34/+ mice. Loss of one Bcl-2 allele did not influence the PKD1del34 phenotype significantly. We conclude that loss of PKD1 and loss of Bcl-2 elicit PKD through distinct mechanisms. 相似文献
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Pillois X Gautier T Bouillet B Pais de Barros JP Jeannin A Vergès B Bonnet J Lagrost L 《Journal of lipid research》2012,53(6):1200-1209
Plasma cholesteryl ester transfer protein (CETP) promotes the cholesterol enrichment of apoB-containing lipoproteins (VLDL and LDL) at the expense of HDL. Recent studies demonstrated that apoC1 is a potent CETP inhibitor in plasma of healthy, normolipidemic subjects. Our goal was to establish whether the modulation of CETP activity by apoC1 is influenced by dyslipidemia in patients with documented coronary artery disease (CAD). In the total CAD population studied (n = 240), apoC1 levels correlated negatively with CETP activity, independently of apoE-epsilon, CETP-Taq1B, and apoC1-Hpa1 genotypes. In multivariate analysis, the negative relationship was observed only in normolipidemic patients, not in those with hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia. In the normolipidemic subjects, apoC1 levels were positively associated with higher HDL- to LDL-cholesterol ratio (r = 0.359, P < 0.001). It is concluded that apoC1 as a CETP inhibitor no longer operates on cholesterol redistribution in high-risk patients with dyslipidemia, probably due to increasing amounts of VLDL-bound apoC1, which is inactive as a CETP inhibitor. Patients with dyslipidemia could experience major benefits from treatment with pharmacological CETP inhibitors, which might compensate for blunted endogenous inhibition. 相似文献
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Maureen Voigtlaender Jean-Paul Laclau José Leonardo de Moraes Gon?alves Marisa de Cássia Piccolo Marcelo Zacharias Moreira Yann Nouvellon Jacques Ranger Jean-Pierre Bouillet 《Plant and Soil》2012,352(1-2):99-111