title: Tumor necrosis factor-alpha mediates hemolysis-induced vasoconstriction and the cerebral vasospasm evoked by subarachnoid hemorrhage.
abstract: 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.
authors.affiliation: Department of Angiocardioneurology, Neuromed Institute IRCCS, Pozzilli, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.forename: Alessandro
authors.initials: A
authors.lastname: Frati
authors.forename: Alba
authors.initials: A
authors.lastname: Di Pardo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cifelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gentile
authors.forename: Rosa
authors.initials: R
authors.lastname: Carangi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Landolfi
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Carullo
authors.forename: Umberto
authors.initials: U
authors.lastname: Bettarini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Antenucci
authors.forename: Giada
authors.initials: G
authors.lastname: Mascio
authors.forename: Carla Letizia
authors.initials: CL
authors.lastname: Busceti
authors.forename: Antonella
authors.initials: A
authors.lastname: Notte
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Cantore
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D020744:rac GTP-Binding Proteins