Liệu pháp Hydroxyurea cho mô hình chuột mắc bệnh thiếu máu hồng cầu hình liềm ức chế sự tiến triển của bệnh do phế cầu khuẩn bằng cách điều chỉnh nồng độ E-selectin

Blood - Tập 119 - Trang 1915-1921 - 2012
Jeffrey D. Lebensburger1, Thad Howard1, Yunming Hu2, Tamara I. Pestina1, Geli Gao2, Melissa Johnson3, Stanislav S. Zakharenko4, Russell E. Ware1, Elaine I. Tuomanen2, Derek A. Persons1, Jason W. Rosch2
1Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
2Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN
3Animal Imaging Center, St Jude Children's Research Hospital, Memphis, TN
4Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN

Tóm tắt

Tóm tắt Bệnh thiếu máu hồng cầu hình liềm được đặc trưng bởi tình trạng tan máu mạn tính đi kèm với viêm mạch máu rộng rãi. Tình trạng viêm này cũng góp phần cơ chế làm tăng nguy cơ nhiễm trùng phế cầu khuẩn xâm lấn, có thể gây tử vong. Các phương pháp điều trị hiện tại nhằm giảm các biến chứng tắc mạch bao gồm liệu pháp hydroxyurea mạn tính để kích thích sản xuất hemoglobin thai nhi. Vì hydroxyurea cũng làm giảm bạch cầu, nên cần hiểu biết về tác động của điều trị này đối với việc gây bệnh do phế cầu khuẩn. Sử dụng mô hình chuột thiếu máu hồng cầu hình liềm mắc viêm phổi phế cầu khuẩn và nhiễm trùng huyết, việc tiêm hydroxyurea cho thấy có tác dụng cải thiện đáng kể khả năng sống sót. Liệu pháp hydroxyurea làm giảm sự thoát mạch của bạch cầu trung tính vào phổi bị nhiễm trùng đồng thời với sự giảm đáng kể nồng độ E-selectin trong huyết thanh và trên biểu mô phổi. Tác dụng bảo vệ của hydroxyurea bị mất đi ở những con chuột thiếu hụt E-selectin. Sự giảm nồng độ E-selectin cũng được ghi nhận ở bệnh nhân thiếu máu hồng cầu hình liềm nhận liệu pháp hydroxyurea. Dữ liệu này cho thấy, ngoài việc kích thích sản xuất hemoglobin thai nhi, hydroxyurea làm giảm tương tác giữa bạch cầu và nội mô trong bệnh thiếu máu hồng cầu hình liềm, từ đó tạo ra sự bảo vệ chống lại nhiễm trùng huyết do phế cầu khuẩn gây tử vong.

Từ khóa


Tài liệu tham khảo

Steinberg, 2010, The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up., Am J Hematol, 85, 403 Voskaridou, 2010, The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)., Blood, 115, 2354, 10.1182/blood-2009-05-221333 Platt, 1994, Mortality in sickle cell disease. Life expectancy and risk factors for early death., N Engl J Med, 330, 1639, 10.1056/NEJM199406093302303 Charache, 1996, Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia., Medicine, 75, 300, 10.1097/00005792-199611000-00002 Charache, 1995, Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia., N Engl J Med, 332, 1317, 10.1056/NEJM199505183322001 Steinberg, 2003, Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment., JAMA, 289, 1645, 10.1001/jama.289.13.1645 Wang, 2011, Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)., Lancet, 377, 1663, 10.1016/S0140-6736(11)60355-3 Overturf, 1999, Infections and immunizations of children with sickle cell disease., Adv Pediatr Infect Dis, 14, 191 Zarkowsky, 1986, Bacteremia in sickle hemoglobinopathies., J Pediatr, 109, 579, 10.1016/S0022-3476(86)80216-5 Gill, 1995, Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease., Blood, 86, 776, 10.1182/blood.V86.2.776.bloodjournal862776 Miller, 2007, Hypersusceptibility to invasive pneumococcal infection in experimental sickle cell disease involves platelet-activating factor receptor., J Infect Dis, 195, 581, 10.1086/510626 McCavit, 2011, Increase in invasive streptococcus pneumoniae infections in children with sickle cell disease since pneumococcal conjugate vaccine licensure., J Pediatr, 158, 505, 10.1016/j.jpeds.2010.11.025 Cundell, 1995, Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor., Nature, 377, 435, 10.1038/377435a0 Rosch, 2010, Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease., J Clin Invest, 120, 627, 10.1172/JCI39843 Lebensburger, 2010, Hydroxyurea therapy requires HbF induction for clinical benefit in a sickle cell mouse model., Haematologica, 95, 1599, 10.3324/haematol.2010.023325 Pestina, 2009, Correction of murine sickle cell disease using gamma-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin., Mol Ther, 17, 245, 10.1038/mt.2008.259 Persons, 2003, The degree of phenotypic correction of murine beta thalassemia intermedia following lentiviral-mediated transfer of human gamma-globulin gene is influenced by chromosomal position effects and vector copy number., Blood, 101, 2175, 10.1182/blood-2002-07-2211 Llewellyn, 2009, Nuclear staining with alum hematoxylin., Biotech Histochem, 84, 159, 10.1080/10520290903052899 Fillon, 2006, Platelet-activating factor receptor and innate immunity: uptake of gram-positive bacterial cell wall into host cells and cell-specific pathophysiology., J Immunol, 177, 6182, 10.4049/jimmunol.177.9.6182 Orihuela, 2009, Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models., J Clin Invest, 119, 1638, 10.1172/JCI36759 Garrison, 2010, The p53-target gene puma drives neutrophil-mediated protection against lethal bacterial sepsis., PLoS Pathog, 6, e1001240, 10.1371/journal.ppat.1001240 Earls, 2010, Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome., J Neurosci, 30, 15843, 10.1523/JNEUROSCI.1425-10.2010 Richardson, 2009, Connectivity patterns revealed by mapping of active inputs on dendrites of thalamorecipient neurons in the auditory cortex., J Neurosci, 29, 6406, 10.1523/JNEUROSCI.0258-09.2009 Rosch, 2009, Calcium efflux is essential for bacterial survival in the eukaryotic host., Mol Microbiol, 72, 12, 10.1111/j.1365-2958.2009.06638.x Lacks, 1960, A study of the genetic material determining enzyme in the pneumococcus., Biochim Biophys Acta, 39, 508, 10.1016/0006-3002(60)90205-5 Orihuela, 2004, Microarray analysis of pneumococcal gene expression during invasive disease., Infect Immun, 72, 5582, 10.1128/IAI.72.10.5582-5596.2004 Orihuela, 2004, Tissue-specific contributions of pneumococcal virulence factors to pathogenesis., J Infect Dis, 190, 1661, 10.1086/424596 Heeney, 2008, Hydroxyurea for children with sickle cell disease., Pediatr Clin North Am, 55, 483, 10.1016/j.pcl.2008.02.003 Bullard, 1996, Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice., J Exp Med, 183, 2329, 10.1084/jem.183.5.2329 Munoz, 1997, Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice., J Clin Invest, 100, 2099, 10.1172/JCI119744 Holtzclaw, 2004, Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice., Am J Respir Crit Care Med, 169, 687, 10.1164/rccm.200302-224OC Lammers, 2011, Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule., Immunobiology, 216, 863, 10.1016/j.imbio.2011.02.004 Hankins, 2008, Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea., Pediatr Blood Cancer, 50, 293, 10.1002/pbc.21271 Kaul, 2004, Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice., Am J Physiol Heart Circ Physiol, 287, H293, 10.1152/ajpheart.01150.2003 Kaul, 2006, Robust vascular protective effect of hydroxamic acid derivatives in a sickle mouse model of inflammation., Microcirculation, 13, 489, 10.1080/10739680600778456 Kinney, 1999, Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group., Blood, 94, 1550 Wang, 2001, A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia., J Pediatr, 139, 790, 10.1067/mpd.2001.119590 Karlström, 2009, Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza., J Infect Dis, 199, 311, 10.1086/596051 Johnston, 1991, Pathogenesis of pneumococcal pneumonia., Rev Infect Dis, 13, S509, 10.1093/clinids/13.Supplement_6.S509 Kanavaki, 2012, Adhesion molecules and high-sensitivity C-reactive protein levels in patients with sickle cell beta-thalassanemia., Eur J Clin Invest, 42, 27, 10.1111/j.1365-2362.2011.02551.x Saleh, 1998, Cytokines and soluble adhesion molecules in sickle cell anemia patients during hydroxyurea therapy., Acta Haematol, 100, 26, 10.1159/000040859 Belcher, 2000, Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion., Blood, 96, 2451, 10.1182/blood.V96.7.2451 Ware, 2010, How I use hydroxyurea to treat young patients with sickle cell anemia., Blood, 115, 5300, 10.1182/blood-2009-04-146852 Chang, 2010, GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice., Blood, 116, 1779, 10.1182/blood-2009-12-260513 Solovey, 2004, Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin., Blood, 104, 840, 10.1182/blood-2003-10-3719 Okpala, 2006, Leukocyte adhesion and the pathophysiology of sickle cell disease., Curr Opin Hematol, 13, 40, 10.1097/01.moh.0000190108.62414.06