Tumor necrosis factor-alpha mediates hemolysis-induced vasoconstriction and the cerebral vasospasm evoked by subarachnoid hemorrhage.
Hypertension can lead to subarachnoid hemorrhage and eventually to cerebral vasospasm. It has been suggested that the latter could be the result of oxidative stress and an inflammatory response evoked by subarachnoid hemorrhage. Because an unavoidable consequence of hemorrhage is lysis of red blood cells, we first tested the hypothesis on carotid arteries that the proinflammatory cytokine tumor necrosis factor-alpha contributes to vascular oxidative stress evoked by hemolysis. We observed that hemolysis induces a significant increase in tumor necrosis factor-alpha both in blood and in vascular tissues, where it provokes Rac-1/NADPH oxidase-mediated oxidative stress and vasoconstriction. Furthermore, we extended our observations to cerebral vessels, demonstrating that tumor necrosis factor-alpha triggered this mechanism on the basilar artery. Finally, in an in vivo model of subarachnoid hemorrhage obtained by the administration of hemolyzed blood in the cisterna magna, we demonstrated, by high-resolution ultrasound analysis, that tumor necrosis factor-alpha inhibition prevented and resolved acute cerebral vasoconstriction. Moreover, tumor necrosis factor-alpha inhibition rescued the hemolysis-induced brain injury, evaluated with the method of 2,3,5-triphenyltetrazolium chloride and by the histological analysis of pyknotic nuclei. In conclusion, our results demonstrate that tumor necrosis factor-alpha plays a crucial role in the onset of hemolysis-induced vascular injury and can be used as a novel target of the therapeutic strategy against cerebral vasospasm.
Vecchione
Carmine
C
Department of Angiocardioneurology, Neuromed Institute IRCCS, Pozzilli, Italy.
Frati
Alessandro
A
Di Pardo
Alba
A
Cifelli
Giuseppe
G
Carnevale
Daniela
D
Gentile
Maria Teresa
MT
Carangi
Rosa
R
Landolfi
Alessandro
A
Carullo
Pierluigi
P
Bettarini
Umberto
U
Antenucci
Giovanna
G
Mascio
Giada
G
Busceti
Carla Letizia
CL
Notte
Antonella
A
Maffei
Angelo
A
Cantore
Gian Paolo
GP
Lembo
Giuseppe
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006461:Hemolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D020301:Vasospasm, Intracranial / Q000097:blood / Q000503:physiopathology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D020744:rac GTP-Binding Proteins