Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria

Yeo, Tsin Wen; Lampah, Daniel A.; Gitawati, Retno; Tjitra, Emiliana; Kenangalem, Enny; Piera, Kim A.; Price, Ric N.; Duffull, Stephen B.; Celermajer, David S.; Anstey, Nicholas M.

doi:10.1073/pnas.0805782105

Cited by 253 publications

(351 citation statements)

References 47 publications

(77 reference statements)

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“…57 At a certain point, the compensatory mechanisms can become incapable of maintaining sufficient tissue oxygenation, 58 and irreversible cell and tissue damage will result. 11,59 The substantial evidence of similarities between human and murine CM 24,54 and the direct and indirect evidence of localized cerebral hypoperfusion in human CM 7,15,16,23,60,61 underscore the need to address strategies to reverse cerebral occlusion and hypoperfusion.…”

Section: Hypoxia and Cerebralmentioning

confidence: 99%

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

Hempel

Combes

Hunt

et al. 2011

The American Journal of Pathology

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Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice, and two models of malaria without neurologic signs, P. berghei K173 in CBA mice and P. berghei ANKA in BALB/c mice. Hypoxia was demonstrated in brain sections using intravenous pimonidazole and staining with hypoxia-inducible factor-1␣-specific antibody. Cytopathic hypoxia was studied using poly (ADP-ribose) polymerase-1 (PARP-1) gene knockout mice. The effect of erythropoietin, an oxygen-sensitive cytokine that mediates protection against CM, on cerebral hypoxia was studied in C57BL/6 mice. Numerous hypoxic foci of neurons and glial cells were observed in mice with CM. Substantially fewer and smaller foci were observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1-deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia. These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy.

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Section: Hypoxia and Cerebralmentioning

confidence: 99%

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

Hempel

Combes

Hunt

et al. 2011

The American Journal of Pathology

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“…91 More recently, the role of NO in severe malaria has also implicated the angiogenic factor Ang-2 which is stored in Weibel-Palade bodies (WPB) in endothelial cells and secreted in conjunction with von Willebrand Factor. 92 The decreased vascular NO bioavailability found in severe malaria is proposed to increase exocytosis of WPB with a resultant increase in Ang-2 release. Independently of NO, elevations in Ang-2 in severe malaria are strongly predictive of disease severity, particularly when measured as a ratio with its barrier protective homolog Ang-1.…”

Section: Host Inflammatory Mediatorsmentioning

confidence: 99%

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Gillrie

2016

Tissue Barriers

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Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The hostparasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.

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“…En los pacientes con malaria por P. falciparum se incrementan los niveles séricos de marcadores de activación endotelial, como factor de von Willebrand, quimiocina CXCL8/IL-8, endotelina 1 (ET-1) y angiopoyetina 2, moléculas almacenadas y liberadas de los cuerpos de Webel-Palade de las células endoteliales (35)(36)(37)(38). El aumento de del factor de von Willebrand se asocia con enfermedad grave y sugiere que la exocitosis de los cuerpos de Webel-Palade participa en la patogenia de la malaria, aunque se desconoce el estímulo que activa esta liberación (37).…”

Section: Activación Endotelialunclassified

“…La angiopoyetina 2 (AGN-2) se encuentra elevada en pacientes con malaria grave en comparación con casos no * Tabla elaborada con base en la revisión de (24) complicados y controles sanos. Esta molécula participa en la activación endotelial y aumenta la permeabilidad vascular (38); también se ha observado aumento de ET-1 y la disminución del péptido natriurético de tipo C (36,37). La ET-1 es una molécula vasoconstrictora y amplificadora de la inflamación, mientras el péptido natriurético de tipo C produce relajación vascular y reduce la interacción de leucocitos y plaquetas con el endotelio activado.…”

Section: Activación Endotelialunclassified

Pathogenic mechanisms in Plasmodium falciparum malaria

Vásquez

Tobón

2012

biomedica

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Se presentan los mecanismos patogénicos más conocidos en la infección por Plasmodium falciparum durante la fase eritrocitaria y extraeritrocitaria. La obstrucción vascular, explicada por los fenómenos de secuestro de glóbulos rojos parasitados y la formación de rosetas, mediados por diversos ligandos y receptores endoteliales, además de los procesos inflamatorios instaurados ante la presencia del parásito, son aspectos centrales en la patogenia de la malaria que permiten explicar los procesos de disfunción, daño y muerte celular en diferentes órganos. A partir de eventos como la lesión y la destrucción de eritrocitos, hepatocitos y células endoteliales, la pérdida de integridad del endotelio y la activación de promotores de daño celular y de apoptosis, se explican alteraciones como el aumento de la permeabilidad vascular, la hipoxia y el metabolismo anaerobio, que conducen tanto a lesiones localizadas en órganos como cerebro y pulmón, como a un estado de acidosis generalizada y falla multisistémica.Palabras clave: malaria/etiología, Plasmodium falciparum, inflamación. Pathogenic mechanisms in Plasmodium falciparum malariaThe most recognized pathogenic mechanisms of the infection with Plasmodium falciparum, during both the erythrocytic and exo-erithrocytic stages are presented. Vascular obstruction explained by the sequestration of parasitized red blood cells and erythrocyte rosetting, mediated by different endothelial ligands and receptors, in addition to the inflammatory processes induced by the presence of the parasite, are central aspects in the pathogenesis of malaria that explain the processes of damage, dysfunction and cell death in various organs. Alterations such as increased vascular permeability, hypoxia and anaerobic metabolism leading to localized lesions in organs such as brain and lung, as well as to a generalized acidotic state with multisystem failure can be explained by events such as the injury and destruction of erythrocytes, hepatocytes and endothelial cells, the loss of endothelial integrity, and the activation of cell damage and apoptosis promoters.Key words: Malaria/ethiology, Plasmodium falciparum, inflamation.Los signos y síntomas clínicos en la malaria, o paludismo, expresión del daño ocasionado en diversos órganos y sistemas, se exacerban durante el período de multiplicación del parásito en el eritrocito, mientras que el estadio hepático y la presencia de gametocitos tradicionalmente no se han asociado con la sintomatología. La malaria causa lesiones estructurales y alteraciones funcionales y metabólicas, cuya presentación clínica está en función de la edad, el estado inmunitario y las características genéticas del huésped, y por la especie, el genotipo y la virulencia del parásito. Puede conducir a un cuadro clínico grave el cual casi siempre se observa en las infecciones causadas por Plasmodium falciparum. Las complicaciones informadas con mayor frecuencia incluyen anemia grave, malaria cerebral, síndrome de dificultad respiratoria aguda y falla renal (1); en los últimos años se vien...

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Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria

Cited by 253 publications

References 47 publications

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

CNS Hypoxia Is More Pronounced in Murine Cerebral than Noncerebral Malaria and Is Reversed by Erythropoietin

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

Pathogenic mechanisms in Plasmodium falciparum malaria

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