Page 95 - Read Online

responses in CA lesions and have suggested the role inflammatory responses in the pathogenesis of CA
of the inflammatory processes in the pathogenesis of formation and progression [22,31-41] and have supported the
CAs. For example, the expression and induction of notion that inflammation in arterial walls contributes to
pro-inflammatory factors such as tumor necrosis factor the pathogenesis in human cases. Nuclear factor-kappa
alpha (TNF-α), infiltration of inflammatory cells in B (NF-κB) is a master transcription factor regulating
the CA lesions (mainly macrophages), and the change the induction of various pro-inflammatory genes
in cell population during CA progression or rupture through the activation of responses to nociceptive
were identified. [6-13] Furthermore, comprehensive gene stimuli. [42] Experimental studies have revealed the
expression analyses have revealed the induction of crucial role of NF-κB in the pathogenesis of CAs by
pro-inflammatory genes in lesions such as TNF-α and triggering and regulating the inflammatory processes
the up-regulation of the inflammation-related pathways in lesions [43] [Figure 1]. During CA formation,
through bioinformatics analyses such as antigen many NF-κB-activated cytokines/mediators such as
processing, immune responses, and responses to outward interleukin (IL)-1β, [38] prostaglandinE , [34] TNF-α, [37,40,41]
2
stimuli, which indicated a significant contribution to and reactive oxygen species [44] are induced, and they
the pathogenesis of CAs. [14-16] Comprehensive gene significantly contribute to CA formation and progression.
expression analyses have also identified an increase in Furthermore, NF-κB-targeted pro-inflammatory
extracellular matrix turnover. [17,18] By linkage analyses, genes, including matrix metalloproteinase-9, [26,32]
pro-inflammatory genes or extracellular matrix-related cyclooxygenase-2 (COX-2), [34] inducible nitric
genes positively correlate with CAs. [19-22] However, oxide synthase, [36,39] monocyte chemoattractant
a considerable limitation is present in studies using protein-1 (MCP-1), [31,35] TNF-α, [37,40,41] and IL-1β [38] are
human samples because of the variety of background induced and likewise contribute to CA formation and
characteristics such as the genetics and clinical progression. In addition, the critical contribution of
history. Furthermore, we cannot examine the exact NF-κB to the pathogenesis of CA is demonstrated in
association of each inflammation-related factor with the deficiency of the NF-κB p50 subunit in mouse or
CA progression through pharmacological inhibition the inhibition of the NF-κB transcriptional activity by
or genetic modification. However, the establishment decoy oligonucleotides treatment in the rat, which both
and use of animal CA models [23-27] has overcome these significantly suppress CA formation and progression
intrinsic limitations associated with human samples by inhibiting NF-κB-mediated inflammatory responses
and has greatly advanced our understanding of the in lesions. [33] Importantly, vicious cycles are formed
mechanisms that regulate CA formation, progression, around NF-κB activation in lesions; for example, TNF-α
and rupture. activates NF-κB and then NF-κB transcriptionally
induces TNF-α. Similarly, NF-κB forms the positive
In a rodent model, CAs are induced at the bifurcation feedback loop of the COX-2-prostaglandinE2-EP2-NF-κB
sites of intracranial arteries through an increase in pathway [34,45] [Figure 1], and COX-2 is induced by
hemodynamic stress, which is also a trigger of CA hemodynamic stress loaded on the arterial walls at
formation in human, [28-30] and is achieved by performing bifurcation sites of the intracranial arteries producing
one-sided carotid ligation and inducing systemic prostaglandinE . [34,45] Then synthesized prostaglandinE
2
2
hypertension through salt over-loading. [23-25] Because acts on one of its specific receptor subtypes, EP2,
CAs induced in models share common pathological and further activates NF-κB. Because NF-κB
features with human cases (e.g. disrupted internal elastic transcriptionally induces the COX-2 expression, once
lamina and degenerative changes of the media, including hemodynamic stress activates COX-2, another positive
the loss of medial smooth muscle cells) and also feedback loop between the prostaglandin system and
spontaneous rupture, they highly mimic human CAs and NF-κB is formed [34,45] [Figure 1]. The presence of this
are presumably suitable for examining the mechanisms vicious cycle and positive feedback loops amplifies
underlying CA formation and progression. [23,24] In some and prolongs the triggered inflammatory responses.
models, elastase is injected into the basal cistern to Along with the amplified inflammation, the infiltration
degenerate internal elastic lamina in intracranial of macrophages and other major inflammatory
arteries and to facilitate CA formation and progression cells in the CA walls, which are recruited via the
in combination with induced systemic hypertension NF-κB-induced MCP-1 expression, contributes to
by angiotensin II infusion. [26,27] In this model, induced the further expansion of inflammation in the whole
CAs in mice can rupture at a higher rate than that in arterial walls [31,35,43] [Figure 1]. MCP-1 is first induced
former models; therefore, they can be used to examine in the endothelial cells during CA formation and
the mechanisms regulating CA rupture. [27] recruits macrophages in the arterial walls. [31] Then
recruited macrophages produce various cytokines
Recent experimental studies mainly using animal and tissue-destructive proteinases such as MMP-9
models of CAs [23-26] have clarified the involvement of that contribute to the expansion of inflammation and

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 87