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stages, degeneration of collagen exceeds its synthesis, located within the medial layer of affected vessels,
and when accompanied by excessive degradation and is associated with inflammation. [18] iNOS activity
of other extracellular matrix macromolecules such results in the production of nitric oxide, which is an
as elastin, ultimately favors AAA rupture. Indeed, important factor involved in inflammatory reactions
AAAs exhibit increased local production of enzymes and the preservation of arterial regulation. iNOS is
capable of degrading the extracellular matrix proteins principally expressed in inflammatory cells such as
collagen and elastin. [7-9] Oxidative stress and elevation macrophages, and may impair arterial wall integrity or
of hemodynamic stress lead to degeneration of elastin induce apoptosis. The expression of iNOS is facilitated
or collagen. The activation of Th1 cytokines via in the media and adventitia during the early phase of
interferon gamma and interleukin-6 polymorphism aneurysm formation. The incidence of experimentally
is accelerated. [10,11] The combination of inflammatory induced cerebral aneurysms in iNOS knockout mice is
reactions and inherited vascular fragileness, along with the same as that in control mice, however the aneurysm
environmental factors like advanced age or smoking, size is significantly smaller. [19] This suggests that iNOS
contributes to the formation and augmentation of contribute to aneurysmal augmentation by promoting
AAAs. apoptosis in medial smooth muscle cells. IL-1β is an
inflammatory cytokine which is activated by cleaved
MOLECULAR BIOLOGY OF CEREBRAL caspase 1. IL-1β is also produced in the early phase
ANEURYSM FORMATION of aneurysm formation, mainly by medial smooth
muscle cells. In IL-1β knockout mice, the progression
Multiple inflammatory factors have been identified that of aneurysm development is significantly impaired. [20]
play a crucial role in cerebral aneurysm formation. [12] This means that inflammatory reactions in the arterial
Inflammatory cells such as macrophages, monocytes, wall contribute to aneurysm enlargement and that IL-1β
and T lymphocytes have been found in aneurysm is a significant mediator of this process.
walls. [4,13] The infiltration of leukocytes is related to
the impairment or elimination of collagen fibers. The TUMOR NECROSIS FACTOR‑ALPHA
plasma levels of cytokines, collagenase, and elastase
are elevated in patients with cerebral aneurysms. [14,15] Tumor necrosis factor-alpha has been revealed to
Recently, nuclear factor-kappa B (NF-κB) and tumor have a close connection with several risk factors that
necrosis factor-alpha (TNF-α) have been widely affect aneurysm formation. Remarkable expression in
investigated as potentially key molecules in the aneurysm walls of mRNA for TNF-α has been observed
inflammatory process. NF-κB is a transcription factor in humans. [21,22] In addition, therapeutic administration
that is known to be closely related to inflammation. of a TNF-α inhibitor significantly reduced aneurysm
NF-κB is activated in endothelial cells at the site of formation in rats. [23] There has been some investigation
arterial bifurcation in the early stages of aneurysm into the relationship between TNF-α expression and
formation, which induces hemodynamic stress. [16] aneurysm formation or rupture. Inflammation induced
This activation is attributable to hemodynamic stress by expression of TNF-α leads to the degeneration of
in the affected endothelial cells. It is thought endothelial cells, the internal elastic lamina, and medial
that activated NF-κB incites several downstream smooth muscle. Cerebral aneurysms are stabilized
inflammation-related genes at the transcriptional level. when the expression of TNF-α is reduced, or expression
Monocyte chemoattractant protein-1 (MCP-1) is one of anti-inflammatory cytokines increases, however
target of NF-κB and is an indispensable factor for continuous expression of TNF-α induces aneurysmal
the migration of macrophages to the lesion site. The rupture. [24] TNF-α also increases the permeability of the
transcription of MCP-1 is controlled by NF-κB at the aneurysm wall via cytokine cascades and induces the
cerebral aneurysmal wall. MCP-1 is secreted from the migration of macrophages or neutrophils to inflamed
endothelial cell layer in the early stages of aneurysm endothelial cells. In addition, TNF-α plays a role in
formation and from all layers of the arterial wall in later other pathological manifestations such as modulation
stages. Macrophage infiltration can be suppressed by of the blood-brain barrier, fluid accumulation, and
the use of MCP-1 knockout mice or MCP-1 inhibitor, regulation of intracranial blood flow in aneurysmal
and leads to inhibition of aneurysm formation. [17] subarachnoid hemorrhage. [25] In transgenic mice that
This evidence highlights the significance of MCP-1 are deficient for TNF-α or TNF receptors, susceptibility
and macrophage infiltration. Other factors controlled to nitric oxide is notably increased. [26,27] In mice with
by NF-κB are inducible nitric oxide synthase (iNOS) congenital TNF-α receptor deficiency, the deleterious
and interleukin-1 beta (IL-1β), which are known effects of oxidative stress are increased by traumatic or
as apoptosis-inducing factors. An investigation of ischemic loading, which indicates that stimulation of
experimentally induced cerebral aneurysms in rats antioxidant pathways by TNF-α may provide protection
revealed that apoptosis occurs in smooth muscle cells against odixative damage. [28]

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