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  • Infliximab Suppresses TNF-α Induced Inflammatory Phenotype in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Formation

    Final Number:

    Muhammad S Ali MD; Robert M. Starke MD MSc; Pascal Jabbour MD; Stavropoula I. Tjoumakaris MD; L. Fernando Gonzalez MD; Robert H. Rosenwasser MD, FACS, FAHA; Aaron S. Dumont MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2013 Annual Meeting

    Introduction: Cerebral Aneurysm rupture results in significant morbidity and mortality. TNF-a has been associated with cerebral aneurysms, but potential mechanisms have not been established, and its role in phenotypic modulation is unknown. Therapy targeting TNF-a may represent a novel treatment strategy for cerebral aneurysms.

    Methods: Cultured cerebral VSMC were incubated with increasing concentrations of TNF-a (5 ng/ml and 50 ng/ml) for 24 hours. Cerebral aneurysm induction surgery was performed in rats. Animal were euthanized at 4 weeks for qPCR and immunohistochemical analysis of the circle of Willis. Animals undergoing aneurysm induction and Infliximab (5mg/kg) treatment were compared to animals undergoing aneurysm induction alone and untreated controls.

    Results: In vitro experiments demonstrated suppression of differentiation markers and induction of pro-inflammatory genes. In vivo, TNF-a mRNA and protein expression was significantly elevated following aneurysm induction compared to untreated controls. Expression of inflammatory markers including chemokines (MCP1 and VCAM1), transcription factors (NF-?B, KLF4), matrix remodeling proteins (MMP-2 & 3), IL-1ß and iNOS was also increased. Furthermore, aneurysm induction resulted in phenotypic modulation by decreasing expression of SMC differentiation marker gene SM-a-Actin. Treatment with Infliximab significantly suppressed TNF-a activity, inhibited expression of inflammatory markers, and decreased the number of CD68+ cells during aneurysm formation. Infliximab also reversed phenotypic modulation in vascular SMC following aneurysm induction.

    Conclusions: ??F-a plays a pivotal role in SMC phenotypic modulation with induction of pro-inflammatory genes and inhibition of SMC differentiation marker genes both in cultured cerebral vascular SMC and in vivo following cerebral aneurysm induction. Infliximab promotes anti-inflammatory effects in cerebral vessels by inhibiting TNF-a and suppressing a pro-inflammatory cascade, which has important implications for the mechanisms behind intracranial aneurysm formation and potential therapeutic options.

    Patient Care: Current understanding of aneurysm biology is inadequate. Better understanding the underlying pathology will help us develop non or minimally invasive treatment options for patients.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) the role of cerebral vascular smooth muscle (VSMC) phenotypic modulation in aneurysm formation and progression 2) the role of tumor necrosis factor-alpha in inducing phenotypic modulation in VSMC and inflammatory up-regulation 3) role of Infliximab (a specific TNFa inhibitor) in suppressing inflammatory up-regulation induced by TNFa in vivo


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