Critical role of TNF-α in cerebral aneurysm formation and progression to rupture.

Robert M Starke,Gary K Owens,Pascal M Jabbour,Nigel H Greig,David M Hasan,Stavropoula I Tjoumakaris,L Gonzalez,Aaron S Dumont,Robert H Rosenwasser,Kosuke Wada,Nohra Chalouhi,Kenji Shimada

doi:10.1186/1742-2094-11-77

Abstract

BackgroundAlterations in TNF-α expression have been associated with cerebral aneurysms, but a direct role in formation, progression, and rupture has not been established.MethodsCerebral aneurysms were induced through hypertension and a single stereotactic injection of elastase into the basal cistern in mice. To test the role of TNF-α in aneurysm formation, aneurysms were induced in TNF-α knockout mice and mice pretreated with the synthesized TNF-α inhibitor 3,6′dithiothalidomide (DTH). To assess the role of TNF-α in aneurysm progression and rupture, DTH was started 6 days after aneurysm induction. TNF-α expression was assessed through real-time PCR and immunofluorescence staining.ResultsTNF-α knockout mice and those pre-treated with DTH had significantly decreased incidence of aneurysm formation and rupture as compared to sham mice. As compared with sham mice, TNF-α protein and mRNA expression was not significantly different in TNF-α knockout mice or those pre-treated with DTH, but was elevated in unruptured and furthermore in ruptured aneurysms. Subarachnoid hemorrhage (SAH) occurred between 7 and 21 days following aneurysm induction. To ensure aneurysm formation preceded rupture, additional mice underwent induction and sacrifice after 7 days. Seventy-five percent had aneurysm formation without evidence of SAH. Initiation of DTH treatment 6 days after aneurysm induction did not alter the incidence of aneurysm formation, but resulted in aneurysmal stabilization and a significant decrease in rupture.ConclusionsThese data suggest a critical role of TNF-α in the formation and rupture of aneurysms in a model of cerebral aneurysm formation. Inhibitors of TNF-α could be beneficial in preventing aneurysmal progression and rupture.

Highlights

Alterations in Tumor necrosis factor alpha (TNF-α) expression have been associated with cerebral aneurysms, but a direct role in formation, progression, and rupture has not been established
TNF-α knockout mice, those treated with DTH, and those treated only with vehicle undergoing aneurysm induction had significant increases in systolic blood pressure 7 days after elastase injection that was sustained until 28 days, but was not significantly different between the three cohorts at any time point (Figure 1)
TNF-α knockout mice were 12.4 times and those treated with DTH were 4.1 times less likely to have aneurysm rupture as compared to mice receiving vehicle

Summary

Introduction

Alterations in TNF-α expression have been associated with cerebral aneurysms, but a direct role in formation, progression, and rupture has not been established. Cerebral aneurysm rupture is associated with significant morbidity and mortality [1,2]. A significant number of patients may be treated with microsurgery or endovascular coiling, but intervention is not without the risk of neurological injury [1,2]. Alterations in TNF-α have been associated with cerebral aneurysm in humans [5,6], but a direct role in aneurysm formation or rupture has not been defined. TNF-α is a critical member of the immune system [7] and produces pro-inflammatory alterations in key cells implicated in cerebral aneurysms including macrophages, endothelial and smooth muscle cells [8,9,10]

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