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changes in the internal elastic lamina and media in whereby active inflammation was imaged in vivo in a
IAs. [30,31] rabbit model of common carotid artery aneurysms. This
group utilized a myeloperoxidase-specific paramagnetic
Thrombus formation contrast agent in conjunction with magnetic resonance
Normally, an intact endothelial wall protects the luminal imaging (MRI). Several years ago, Hasan et al. reported
[44]
surface from thrombosis and platelet aggregation, on the use of ferumoxytol-enhanced MRI to image
in part via the expression of CD39, nitric oxide, and macrophages within aneurysm walls in 11 patients
prostacyclin. [32] In contrast, damaged or denuded with unruptured IAs. Ferumoxytol is an iron oxide
endothelial cells may instead activate thrombosis and nanoparticle theoretically macrophage-selective as it
platelet aggregation pathways. Altered hemodynamic is cleared by reticuloendothelial system macrophages.
flow within the IA cavity may also promote Interestingly, early ferumoxytol-associated imaging
thrombus formation. [33] Neutrophils and macrophages changes (24 h postinfusion) were identified in
are recruited to the site of endothelial injury and five patients, and several of these patients had
thrombosis. These cells often release proteolytic “symptomatic” IAs (progressive headache; rapid
enzymes, MMPs, cathepsin G, and elastase, to try aneurysmal enlargement; aneurysm rupture). Further
and promote fibrinolysis and thrombus degradation. studies with larger sample sizes are needed to confirm
Instead, these proteolytic enzymes may further degrade whether ferumoxytol-associated imaging changes
the IA wall. [34] SMCs and myofibroblasts may invade correlate with greater IA rupture risk.
the thrombus, incorporating the thrombus into the IA
wall itself. [35] POTENTIAL ANTI‑INFLAMMATORY
PHARMACOLOGIC TARGETS
Complement cascade
The complement cascade has also been studied as a Advances in our understanding of the inflammatory
contributor to the pathogenesis of IAs. Activation of cascade leading to aneurysm destabilization and
complement leads to robust and efficient proteolytic rupture may result in the designing of novel therapies
cascades, typically terminating in opsonization individualized to specific patients. Preliminary data
and lysis of pathogens as well as in the generation in animal models of IA suggest therapies targeting the
of the classic inflammatory response through the inflammatory response may have efficacy in the future
production of potent pro-inflammatory molecules. treatment of IA. For instance, in their rat model of
Immunostaining of IA walls both in humans and animal IA, Aoki et al. [45,46] demonstrated reduction of IA wall
models have identified complement components, inflammation and cessation of aneurysm progression
[36]
particularly C3 and C9. Two studies using microarray via various statin agents. The expression of MCP-1,
analysis have demonstrated variable expression of VCAM-1, IL-1β, inducible nitric oxide synthase,
complement-related genes in IAs as compared with and MMP-9 were all reduced in statin-treated rats,
control arterial tissue. [37,38] And in another study likely via inhibition of NF-κB. However, other studies
comparing ruptured with unruptured aneurysms, the have demonstrated dose-dependent effects of statins
expression of the complement cascade end product (the on IAs, including aneurysm growth and/or rupture
membrane attack complex) was greater in ruptured with high doses of statins. [47] A case-control study
samples and correlated significantly with aneurysm by Marbacher et al. [48] did not find a reduction in the
wall degeneration and inflammatory cell infiltration. [39] incidence of IAs in patients with a history of statin
It continues to be unclear, though, how complement use. Additional prospective studies are needed to
activation results in IA rupture, further studies are clarify the role statins may play in patients with IAs.
needed to define the exact pathways linking the two. Other promising therapeutics include edavarone, a
synthetic free radical scavenger, and nifedipine, a
IMAGING OF ARTERIAL WALL INFLAMMATION calcium channel antagonist. [45,49] In an experimental
model of IA, nifedipine inhibited DNA binding of
Noninvasive imaging of vascular inflammation within NF-κB, preventing progression of IA wall degeneration
the aneurysm wall may in the future help differentiate and limiting IA size.
stable IAs from destabilized IAs at greater risk for
rupture. For instance, protocols have been developed Recently, aspirin has emerged as a candidate for
to visualize arterial wall inflammation in patients noninvasive pharmacotherapy in patients with
with intracranial atherosclerosis. Preliminary studies unruptured IAs. Depending on the dose, aspirin
of atherosclerotic plaques suggest vulnerable plaques can inhibit several inflammatory mediators via its
prone to rupture have arterial wall imaging profiles irreversible inhibition of cyclooxygenase-2. Among
separate from stable, asymptomatic plaques. [40-42] patients enrolled in ISUIA, those with a history of aspirin
Regarding IAs, DeLeo et al. [43] published a pilot study use 3 times weekly, or greater had a lower risk of cerebral

104 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015