Vasculopathy and pulmonary hypertension in sickle cell disease

American Journal of Physiology - Lung Cellular and Molecular Physiology

Volumn 308, Issue 4, 2015, Pages L314-L324

  Potoka, Karin P ^a,b   Gladwin, Mark T ^a,b  

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Cell free hemoglobin; Nitric oxide; Pulmonary hypertension; Sickle cell disease

Indexed keywords

HEME; HEMOGLOBIN; HYDROXYUREA; NITRIC OXIDE; PROSTACYCLIN; REACTIVE OXYGEN METABOLITE; SELEXIPAG; SILDENAFIL; HEMOGLOBIN S; TLR4 PROTEIN, HUMAN; TOLL LIKE RECEPTOR 4;

ARTICLE; CLINICAL FEATURE; CONTINUOUS INFUSION; ENDOTHELIAL DYSFUNCTION; ERYTHROCYTE TRANSFUSION; HEMOLYSIS; HEMOLYTIC ANEMIA; HUMAN; INNATE IMMUNITY; NONHUMAN; PREVALENCE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RISK FACTOR; SICKLE CELL ANEMIA; THROMBOCYTE ACTIVATION; VASCULAR DISEASE; ACUTE CHEST SYNDROME; AGE; BLOOD; ERYTHROCYTE DISORDER; GENETICS; HEART FAILURE; HYPERTENSION, PULMONARY; IMMUNOLOGY; METABOLISM; MUTATION; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRACTICE GUIDELINE; RENAL INSUFFICIENCY, CHRONIC; VASCULAR DISEASES; VASCULAR RESISTANCE;

ACUTE CHEST SYNDROME; AGE FACTORS; ERYTHROCYTES, ABNORMAL; HEART FAILURE; HEME; HEMOGLOBIN, SICKLE; HEMOLYSIS; HUMANS; HYPERTENSION, PULMONARY; IMMUNITY, INNATE; MUTATION; NITRIC OXIDE; OXIDATIVE STRESS; PRACTICE GUIDELINES AS TOPIC; REACTIVE OXYGEN SPECIES; RENAL INSUFFICIENCY, CHRONIC; TOLL-LIKE RECEPTOR 4; VASCULAR DISEASES; VASCULAR RESISTANCE;

EID: 84922971966     PISSN: 10400605     EISSN: 15221504     Source Type: Journal    
DOI: 10.1152/ajplung.00252.2014     Document Type: Article

References (95)

1. Anthi A, Machado RF, Jison ML, Taveira-Dasilva AM, Rubin LJ, Hunter L, Hunter CJ, Coles W, Nichols J, Avila NA, Sachdev V, Chen CC, Gladwin MT. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med 175: 1272-1279, 2007.
2. Aslan M, Ryan TM, Adler B, Townes TM, Parks DA, Thompson JA, Tousson A, Gladwin MT, Patel RP, Tarpey MM, Batinic-Haberle I, White CR, Freeman BA. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci USA 98: 15215-15220, 2001.
3. Aslan M, Ryan TM, Townes TM, Coward L, Kirk MC, Barnes S, Alexander CB, Rosenfeld SS, Freeman BA. Nitric oxide-dependent generation of reactive species in sickle cell disease. Actin tyrosine induces defective cytoskeletal polymerization. J Biol Chem 278: 4194-4204, 2003.
4. Ataga KI, Brittain JE, Desai P, May R, Jones S, Delaney J, Strayhorn D, Hinderliter A, Key NS. Association of coagulation activation with clinical complications in sickle cell disease. PLoS One 7: e29786, 2012.
5. Ataga KI, Moore CG, Hillery CA, Jones S, Whinna HC, Strayhorn D, Sohier C, Hinderliter A, Parise LV, Orringer EP. Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. Haematologica 93: 20-26, 2008.
6. Ataga KI, Sood N, De Gent G, Kelly E, Henderson AG, Jones S, Strayhorn D, Lail A, Lieff S, Orringer EP. Pulmonary hypertension in sickle cell disease. Am J Med 117: 665-669, 2004.
7. Baek JH, D'Agnillo F, Vallelian F, Pereira CP, Williams MC, Jia Y, Schaer DJ, Buehler PW. Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy. J Clin Invest 122: 1444-1458,2012.
8. Barnett CF, Machado RF. Sildenafil in the treatment of pulmonary hypertension. Vasc Health Risk Management 2: 411-422, 2006.
9. Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, Naeije R, Sood N, Swerdlow PS, Hildesheim M, Gladwin MT; ASSET Study Group. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosen-tan: results of the ASSET studies. Br J Haematol 149: 426-435, 2010.
10. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jobsis MM, Blackburn SD, Shortino D, Crow JW; and Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334: 296-301, 1996.
11. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, Shao Z, Canver MC, Smith EC, Pinello L, Sabo PJ, Vierstra J, Voit RA, Yuan GC, Porteus MH, Stamatoyannopoulos JA, Lettre G, Orkin SH. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342: 253-257.
12. Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, Smith A, Nath KA, Hebbel RP, Vercellotti GM. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123: 377-390.
13. Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood 96: 2451-2459., 2000.
14. Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ; and Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial Study Group. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase lib double-blind, randomized, placebo-controlled, dose-ranging hemody-namic study. Circulation 128: 502-511, 2013.
15. Boutaud O, Moore KP, Reeder BJ, Harry D, Howie AJ, Wang S, Carney CK, Masterson TS, Amin T, Wright DW, Wilson MT, Oates JA, Roberts LJ 2nd. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc Natl Acad Sci USA 107: 2699-2704, 2010.
16. Buehler PW, Baek JH, Lisk C, Connor I, Sullivan T, Kominsky D, Majka S, Stenmark KR, Nozik-Grayck E, Bonaventura J, Irwin DC. Free hemoglobin induction of pulmonary vascular disease: evidence for an inflammatory mechanism. Am J Physiol Lung Cell Mol Physiol 303: L312-L326, 2012.
17. Bum-Yong YK, Park KK, Tan F, Sutliff RL, Ofori-Acquah SF, Hart CM. MicroRNA-27a and PPARgamma regulate endothelin signaling in sickle cell disease-related pulmonary hypertension. FASEB J 26: 873.872, 2012.
18. Bunn HF. Pathogenesis and treatment ofsickle cell disease. NEngl JMed 337: 762-769, 1997.
19. Castro O, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 101: 12571261, 2003.
20. Channick RN, Newhart JW, Johnson FW, Williams PJ, Auger WR, Fedullo PF, Moser KM. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. Chest 109: 1545-1549, 1996.
21. Chantrathammachart P, Mackman N, Sparkenbaugh E, Wang JG, Parise LV, Kirchhofer D, Keys NS, Pawlinski R. Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease. Blood 120: 636-646, 2012.
22. Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 123: 3818-3827, 2014.
23. De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A, Telen MJ. Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol 83: 19-25, 2008.
24. de Jong K, Emerson RK, Butler J, Bastacky J, Mohandas N, Kuypers FA. Short survival of phosphatidylserine-exposing red blood cells in murine sickle cell anemia. Blood 98: 1577-1584, 2001.
25. Donadee C, Raat NJ, Kanias T, Tejero J, Lee JS, Kelley EE, Zhao X, Liu C, Reynolds H, Azarov I, Frizzell S, Meyer EM, Donnenberg AD, Qu L, Triulzi D, Kim-Shapiro DB, Gladwin MT. Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation 124: 465-476, 2011.
26. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cy-clase: discovery and therapeutic potential. Nat Rev Drug Discovery 5:755-768, 2006.
27. Fabry ME, Sengupta A, Suzuka SM, Costantini F, Rubin EM, Ho-frichter J, Christoph G, Manci E, Culberson D, Factor SM, Nagel RL. A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-Antilles results in increased phenotypic severity. Blood 86: 2419-2428, 1995.
28. Fonseca GH, Souza R, Salemi VM, Jardim CV, Gualandro SF. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J 39: 112-118, 2012.
29. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; and Sildenafil Use in Pulmonary Arterial Hypertension Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353: 2148-2157, 2005.
30. Galie N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med 2: 123-137, 2003.
31. Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369: 319-329, 2013.
32. Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369: 330-340, 2013.
33. Ghosh S, Adisa OA, Chappa P, Tan F, Jackson KA, Archer DR, Ofori-Acquah SF. Extracellular hemin crisis triggers acute chest syndrome in sickle mice. J Clin Invest 123: 4809-4820, 2013.
34. Gladwin MT, Kato GJ, Weiner D, Onyekwere OC, Dampier C, Hsu L, Hagar RW, Howard T, Nuss R, Okam MM, Tremonti CK, Berman B, Villella A, Krishnamurti L, Lanzkron S, Castro O, Gordeuk VR, Coles WA, Peters-Lawrence M, Nichols J, Hall MK, Hildesheim M, Blackwelder WC, Baldassarre J, Casella JF, De NI. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 305: 893-902, 2011.
35. Gladwin MT, Ofori-Acquah SF. Erythroid DAMPs drive inflammation in SCD. Blood 123: 3689-3690, 2014.
36. Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol 59: 1123-1133, 2012.
37. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350: 886-895, 2004.
38. Gladwin MT, Schechter AN, Ognibene FP, Coles WA, Reiter CD, Schenke WH, Csako G, Waclawiw MA, Panza JA, Cannon RO 3rd. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 107: 271-278, 2003.
39. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 359: 2254-2265, 2008.
40. Gordeuk VR, Minniti CP, Nouraie M, Campbell AD, Rana SR, Luchtman-Jones L, Sable C, Dham N, Ensing G, Prchal JT, Kato GJ, Gladwin MT, Castro OL. Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia. Haematologica 96: 33-40, 2011.
41. Gordeuk VR, Sachdev V, Taylor JG, Gladwin MT, Kato G, Castro OL. Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. Am J Hematol 83: 15-18, 2008.
42. Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood 92: 2551-2555, 1998.
43. Hellstrom WJ, Overstreet JW, Yu A, Saikali K, Shen W, Beasley CM Jr., Watkins VS. Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. J Urol 170: 887-891, 2003.
44. Helms CC, Marvel M, Zhao W, Stahle M, Vest R, Kato GJ, Lee JS, Christ G, Gladwin MT, Hantgan RR, Kim-Shapiro DB. Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost 11: 2148-2154, 2013.
45. Hsu LL, Champion HC, Campbell-Lee SA, Bivalacqua TJ, Manci EA, Diwan BA, Schimel DM, Cochard AE, Wang X, Schechter AN, Noguchi CT, Gladwin MT. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 109: 3088-3098, 2007.
46. Kato GJ, Gladwin MT. Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy. JAMA 300: 2638-2646, 2008.
47. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 21: 37-47, 2007.
48. Kato GJ, Martyr S, Blackwelder WC, Nichols JS, Coles WA, Hunter LA, Brennan ML, Hazen SL, Gladwin MT. Levels of soluble endothe-lium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality. Br J Haematol 130: 943-953, 2005.
49. Kato GJ, McGowan V, Machado RF, Little JA, Taylor Jt Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 107: 2279-2285, 2006.
50. Kato GJ, Nouraie SM, Gladwin MT. Lactate dehydrogenase and hemo-lysis in sickle cell disease. Blood 122: 1091-1092, 2013.
51. Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest 106: 411-420, 2000.
52. Kaul DK, Liu XD, Chang HY, Nagel RL, Fabry ME. Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. J Clin Invest 114: 1136-1145, 2004.
53. Kaul DK, Liu XD, Fabry ME, Nagel RL. impaired nitric oxide-mediated vasodilation in transgenic sickle mouse. Am J Physiol Heart Circ Physiol 278: H1799-H1806, 2000.
54. Klings ES, Machado RF, Barst RJ, Morris CR, Mubarak KK, Gor-deuk VR, Kato GJ, Ataga KI, Gibbs JS, Castro O, Rosenzweig EB, Sood N, Hsu L, Wilson KC, Telen MJ, Decastro LM, Krishnamurti L, Steinberg MH, Badesch DB, Gladwin MT. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am J Respir Crit Care Med 189: 727-740, 2014.
55. Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ, Taveira-DaSilva AM, Ballas SK, Blackwelder W, Xu X, Hunter L, Barton B, Waclawiw M, Castro O, Gladwin MT. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA 296: 310-318, 2006.
56. Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, Gibbs JS, Little JA, Schraufnagel DE, Krishnamurti L, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Onyekw-ere O, Castro OL, Sachdev V, Waclawiw MA, Woolson R, Goldsmith JC, Gladwin MT; walk-PHaSST investigators and Patients. Hospitaliza-tion for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 118: 855-864, 2011.
57. Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR, Hunter L, Coles W, Nichols J, Hunter C, Sachdev V, Castro O, Gladwin MT. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol 130: 445-453, 2005.
58. Manci EA, Hillery CA, Bodian CA, Zhang ZG, Lutty GA, Coller BS. Pathology of Berkeley sickle mice: similarities and differences with human sickle cell disease. Blood 107: 1651-1658, 2006.
59. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237-241, 2006.
60. Mehari A, Alam S, Tian X, Cuttica MJ, Barnett CF, Miles G, Xu D, Seamon C, Adams-Graves P, Castro OL, Minniti CP, Sachdev V, Taylor JG 6th, Kato GJ, Machado RF. Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med 187: 840-847, 2013.
61. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307: 1254-1256, 2012.
62. Mekontso Dessap A, Leon R, Habibi A, Nzouakou R, Roudot-Thora-val F, Adnot S, Godeau B, Galacteros F, Brun-Buisson C, Brochard L, Maitre B. Pulmonary hypertension and cor pulmonale during severe acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 177: 646-653, 2008.
63. Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, Foglio M, Zelenika D, Boland A, Rooks H, Best S, Spector TD, Farrall M, Lathrop M, Thein SL. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet 39: 1197-1199, 2007.
64. Minniti CP, Machado RF, Coles WA, Sachdev V, Gladwin MT, Kato GJ. Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. Br J Haematol 147: 737-743, 2009.
65. Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, Onyekwere O, Nouraie M, Kato GJ, Gladwin MT, Castro OL, Gor-deuk VR. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 94: 340-347, 2009.
66. Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294: 81-90, 2005.
67. Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 168: 63-69, 2003.
68. Nath KA, Shah V, Haggard JJ, Croatt AJ, Smith LA, Hebbel RP, Katusic ZS. Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease. Am J Physiol Regul Integr CompPhysiol 279: R1949-R1955, 2000.
69. Noguchi CT, Gladwin M, Diwan B, Merciris P, Smith R, Yu X, Buzard G, Fitzhugh A, Keefer LK, Schechter AN, Mohandas N. Pathophysiology of a sickle cell trait mouse model: human alpha(beta)(S) transgenes with one mouse beta-globin allele. Blood Cells Mol Dis 27: 971-977, 2001.
70. Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, Oriss TB, Zeng Q, Kato GJ, Gibbs JS, Hildesheim ME, Sachdev V, Barst RJ, Machado RF, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli E, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Castro OL, Goldsmith JC, Gordeuk VR, Gladwin MT. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica 98: 464-472, 2013.
71. Olson JS, Foley EW, Rogge C, Tsai AL, Doyle MP, Lemon DD. No scavenging and the hypertensive effect of hemoglobin-based blood substitutes. Free Radic Biol Med 36: 685-697, 2004.
72. Osarogiagbon UR, Choong S, Belcher JD, Vercellotti GM, Paller MS, Hebbel RP. Reperfusion injury pathophysiology in sickle transgenic mice. Blood 96: 314-320, 2000.
73. Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, Habibi A, Bennani S, Savale L, Adnot S, Maitre B, Yai'ci A, Hajji L, O'Callaghan DS, Clerson P, Girot R, Galacteros F, Simonneau G. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 365: 44-53, 2011.
74. Paszty C, Brion CM, Manci E, Witkowska HE, Stevens ME, Mohandas N, Rubin EM. Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease. Science 278: 876-878, 1997.
75. Paszty C, Mohandas N, Stevens ME, Loring JF, Liebhaber SA, Brion CM, Rubin EM. Lethal alpha-thalassaemia created by gene targeting in mice and its genetic rescue. Nat Genet 11: 33-39, 1995.
76. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death [see comments]. N Engl J Med 330: 1639-1644, 1994.
77. Qin X, Hu W, Song W, Blair P, Wu G, Hu X, Song Y, Bauer S, Feelisch M, Leopold JA, Loscalzo J, Halperin JA. Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice. Am J Hematol 84: 221-227, 2009.
78. Raat NJ, Tabima DM, Specht PA, Tejero J, Champion HC, Kim-Shapiro DB, Baust J, Mik EG, Hildesheim M, Stasch JP, Becker EM, Truebel H, Gladwin MT. Direct sGC activation bypasses NO scavenging reactions of intravascular free oxy-hemoglobin and limits vasoconstric-tion. Antioxidants Redox Signal 19: 2232-2243, 2013.
79. Reeder BJ, Wilson MT. Hemoglobin and myoglobin associated oxidative stress: from molecular mechanisms to disease States. Curr Med Chem 12: 2741-2751, 2005.
80. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 376:2018-2031, 2010.
81. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8: 1383-1389, 2002.
82. Rivera A, Jarolim P, Brugnara C. Modulation of Gardos channel activity by cytokines in sickle erythrocytes. Blood 99: 357-603, 2002.
83. Rivera A, Rotter MA, Brugnara C. Endothelins activate Ca2+-gated K+ channels via endothelin B receptors in CD-1 mouse erythrocytes. Am J Physiol Cell Physiol 277: C746-C754, 1999.
84. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293: 1653-1662, 2005.
85. Rubin LJ, Badesch DB, Fleming TR, Galie N, Simonneau G, Ghofrani HA, Oakes M, Layton G, Serdarevic-Pehar M, McLaughlin VV, Barst RJ; SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 140: 1274-1283, 2011.
86. Ryan TM, Ciavatta DJ, Townes TM. Knockout-transgenic mouse model of sickle cell disease. Science 278: 873-876, 1997.
87. Saraf SL, Zhang X, Kanias T, Lash JP, Molokie RE, Oza B, Lai C, Rowe JH, Gowhari M, Hassan J, Desimone J, Machado RF, Gladwin MT, Little JA, Gordeuk VR. Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia. Br J Haematol 164: 729-739, 2014.
88. Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, Degano B, Bonderman D, Kurzyna M, Efficace M, Giorgino R, Lang IM. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 40: 874-880, 2012.
89. Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, Saned MS, El-Chafic AH, Fasulo MR, Cappellini MD. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTiMAL CARE study. Blood 115: 1886-1892, 2010.
90. Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet 18: R216-R223, 2009.
91. Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 110: 2166-2172, 2007.
92. Wang X, Mendelsohn L, Rogers H, Leitman S, Raghavachari N, Yang Y, Yau YY, Tallack M, Perkins A, Taylor JGt Noguchi CT, Kato GJ. Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Kruppel-like factor. Blood 124: 946-954, 2014.
93. Wood KC, Hsu LL, Gladwin MT. Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radic Biol Med 44: 1506-1528, 2008.
94. Yang B, Kirby S, Lewis J, Detloff PJ, Maeda N, Smithies O. A mouse model for 30-thalassemia. Proc Natl Acad Sci USA 92: 11608-11612, 1995.
95. Zhang X, Fabry ME, Suzuka SM, Kaul DK. Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1a expression in normoxic sickle mice: microvascular implications. Am J Physiology Heart Circ Physiology 304: H42-H50, 2013.