Inhaled Nitric Oxide for Treatment of Sickle Cell Stroke

Montero-Huerta, Pedro; Hess, Dean; Head, C. Alvin

doi:10.1097/00000542-200609000-00028

Cited by 11 publications

(4 citation statements)

References 14 publications

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“…11 Research over recent years indicates that reduced nitric oxide (NO) bioavailability may contribute to manifestations of SCD, such as pulmonary hypertension and cutaneous leg ulceration. 12,13 Whether reduced NO signaling has a direct role in the vasoocclusive process is currently unknown; however, several studies indicate that nitric oxide-based therapies may be beneficial for increasing regional blood flow, 14 reducing pain, 15 and treating stroke 16 in SCD. Furthermore, studies demonstrate that elevation of NO, or supplementation of its substrate, arginine, can reduce SCD neutrophil adhesive properties in vitro, and can improve microvascular functions, 17 increase survival, and prevent lung injury during hypoxia in SCD mice.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Almeida

Scheiermann

Jang

et al. 2012

Blood

116

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Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-␣-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobinelevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease. (Blood. 2012;120(14): 2879-2888) IntroductionSickle cell disease (SCD) is a genetic disorder caused by a point mutation in the HBB gene, resulting in the production of abnormal sickle hemoglobin (HbS). 1,2 HbS polymerizes at low oxygen levels, making the red blood cell (RBC) more rigid and, eventually, irreversibly sickled. This causes the complex pathophysiology of SCD that includes hemolysis, chronic inflammation, elevated cell adhesion, leukocytosis, increased oxidative stress, and endothelial activation/dysfunction, which can culminate in the acute vasoocclusive processes that are responsible for much of the morbidity observed in patients. 1,2 Vaso-occlusion comprises multistep and multicellular processes that appear to be initiated by the adhesion of red cells and leukocytes to activated endothelium via a mechanism in which inflammation, hypoxic events, oxidative stress, and reduced nitric oxide availability probably play roles. [3][4][5][6][7] Data from in vivo studies using SCD mice 5,8,9 and in vitro studies 10 indicate that the recruitment of large, less deformable leukocytes to the vessel wall, and their subsequent interactions with circulating RBCs, may initiate vaso-occlusion. As such, drugs that inhibit the adhesion of leukocytes to vascular endothelium may represent an important approach for decreasing, or even preventing, vaso-occlusion. 11 Research over recent years indicates that reduced nitric oxide (NO) bioavailability may contribute to manifestations of SCD, such as pulmonary hypertension and cutaneous leg ulceration. 12,13 Whether reduced NO signaling has a direct role in the vasoocclusi...

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Section: Introductionmentioning

confidence: 99%

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Almeida

Scheiermann

Jang

et al. 2012

Blood

116

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“…4,8,9 These findings have led some clinicians to treat SCD patients suffering from vasoocclusive crisis (VOC), ACS, and stroke with inhaled NO. [10][11][12][13][14] Decreased concentrations of NO in exhaled breath (FE NO ) have also been observed in adults and children with SCD during baseline health and acute illness, 15,16 but the physiologic importance of this finding is not clear. We have shown earlier that diminished FE NO and predilection to ACS in children with SCD are associated with a polymorphism in the nitric oxide synthase-1 (NOS-1) gene and impaired spirometry.…”

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confidence: 99%

Effect of Oral Arginine Supplementation on Exhaled Nitric Oxide Concentration in Sickle Cell Anemia and Acute Chest Syndrome

Sullivan¹,

Kissoon

Sandler³

et al. 2010

Journal of Pediatric Hematology/Oncology

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In contrast to our earlier study, ACS+ patients had similar FE(NO) values when compared with ACS- and HC patients. All SCD patients were arginine deficient at baseline and showed impairment in respiratory physiology when compared with HC patients. After arginine supplementation, FE(NO) concentration increased in all groups to a similar degree, and lung function and physiologic parameters were minimally affected. The physiologic significance of alterations in FE(NO) in SCD patients and its relationship to ACS predilection requires further delineation.

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“…Leukocytosis is frequently observed in SCD and elevated leukocyte counts are associated with increased mortality, constituting a risk factor for crisis, acute chest syndrome and stroke. 4,[18][19][20] In addition, white cell adhesion to the vessel wall may play an initiating role in the vaso-occlusive process. 3 As such, an understanding of the mechanisms that contribute to increase leukocyte counts in the circulation is imperative, as is the comprehension of cell survival and death pathways in SCD.…”

Section: Discussionmentioning

confidence: 99%

“…14 Research over recent years indicates that decreased nitric oxide (NO) bioavailability, due to mechanisms that include cell-free hemoglobin NO scavenging, may contribute to manifestations of SCD such as pulmonary hypertension and cutaneous leg ulceration. 15,16 Whether reduced NO signaling has a direct role in the vaso-occlusive process is currently unknown; however a number of studies indicate that nitric oxide-based therapies may be beneficial for increasing regional blood flow, 17 reducing pain 18 and treating stroke 19 in SCD. Furthermore, studies demonstrate that elevation of NO, or supplementation of its substrate, arginine, can reduce SCD neutrophil adhesive properties in vitro, and can improve microvascular function, 20 increase survival and prevent lung injury during hypoxia 21,22 in sickle mice.…”

Section: Introductionmentioning

confidence: 99%

Papel dos leucócitos na fisiopatologia da anemia falciforme

Almeida¹

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Agradeço im ensam ent e a t odos aqueles que m e aj udaram na realização desse t rabalho: À Dra Nicola Conran que deposit ou t ant a confiança em m im . Muit o obrigada pela paciência, am izade, ensinam ent os im precindíveis e incent ivos const ant es na m inha form ação com o pesquisadora.Ao Dr Fernando Ferreira Cost a pelo apoio e pelas soluções.Ao Dr Paul Frenet t e pelos ensinam ent os e pela oport unidade de adquirir experiência em seu laborat ório.À She, m inha grande am iga, com panheira em t odos os m om ent os, que m e acolheu quando precisei e m e aguent ou por t ant o t em po! À Flavia, sem pre dispost a a t udo, foi e sem pre será um a delícia com part ilhar as risadas com você! À Babi e Cam ila nem m esm o o t em po, nem a dist ância, nunca nos separarão! Às m inhas am igas de t odas as horas, inclusive alm oços, Renat a, Ana Flavia e Carol, é m uit o gost oso com part ilhar experiências de vida, de t rabalho, enfim de t udo, com vocês! ! ! Ao com panheirism o das am izades nascidas no laborat ório. Ao Anderson, grande am igo e com panheiro de t odas as horas; à Venina, et erna desbravadora de t erras áridas; à Lediana, grande bat alhadora; à Em ília, vendedora de experiência; à Carla, present e nos m om ent os chave; à Ucha, sem pre preparada para t odos os churrascos. À Fernanda e Ana Leda pelo apoio na cit om et ria.Aos dem ais m em bros do laborat ório pela harm onia na convivência diária. À Fernanda,

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Inhaled Nitric Oxide for Treatment of Sickle Cell Stroke

Cited by 11 publications

References 14 publications

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Effect of Oral Arginine Supplementation on Exhaled Nitric Oxide Concentration in Sickle Cell Anemia and Acute Chest Syndrome

Papel dos leucócitos na fisiopatologia da anemia falciforme

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