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|NI FEATURE: THE EDITORIAL DEBATE II-- PROS AND CONS
|Year : 2017 | Volume
| Issue : 4 | Page : 706-707
Inflammation and aneurysms
Department of Neurological Surgery, Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
|Date of Web Publication||5-Jul-2017|
Department of Neurological Surgery, Jaslok Hospital and Research Centre, 15, Dr. Deshmukh Marg, Mumbai - 400 026, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Ambekar S. Inflammation and aneurysms. Neurol India 2017;65:706-7
Subarachnoid hemorrhage due to an intracranial aneurysm (IA) rupture is a devastating condition. Approximately 40–50% of the patients with intracranial aneurysmal rupture die, and one-third are left with permanent neurological deficits. Recent research has focused on the interplay between blood flow hemodynamics, inflammation, and morphology of IAs and their effects on the formation, growth, and rupture of IAs. The role of inflammation in IA formation, growth, and rupture is being increasingly recognized in the recent years. The fact that the inflammatory cascade is likely interrelated with mechanical flow-induced vascular dysfunction leading to aneurysm destabilization and rupture has also been shown in recent studies.
In the article “Molecular mechanism of the association between the long non-coding RNA ANRIL and intracranial aneurysms,” the authors review the various inflammatory molecules that have been implicated in the pathogenesis of IA. ANRIL or Antisense Noncoding RNA in the INK Locus is a long intergenic noncoding ribonucleic acid (RNA) located on chromosome 9p, whose deletion leads to greater suppression of RNA encoded by Cdkn2a and Cdkn2b. Smooth muscle cells from mice containing mutant ANRIL have increased proliferative activity.
Excessive shear stress leading to endothelial dysfunction seems to be the initial mechanism in IA formation. Flow-mediated endothelial dysfunction leads to the activation of inflammatory mediators such as nuclear factor-kappa B, proinflammatory cytokines, and cell adhesion molecules. Monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and vascular cell adhesion molecule-1 (VCAM-1) are also expressed on the endothelial surface., These inflammatory molecules attract mononuclear cells, monocytes, and T cells from peripheral blood that adhere and transmigrate into the endothelium and form macrophages leading to the cycle of arterial wall destruction and remodeling, thus, initiating aneurysm formation. During remodeling, the intima, media and the internal elastic lamina are destroyed leading to aneurysm growth. High wall shear stress (WSS) and positive WSS gradient have been demonstrated to lead to matrix metalloproteinase protein production by the mural cells, endothelial cell degradation, medial thinning, and mural cell apoptosis; whereas low WSS and high oscillatory shear index (OSI) leads to endothelial cell dysfunction, increased reactive oxygen species, increased inflammatory cell infiltration, smooth muscle cell proliferation, and migration and thrombus formation. The presence of estrogen receptor beta (ER-β) in human IAs and cerebral arteries possibly explains the protective effect of estrogen in premenopausal women. The protective effect of ER-β is dependent on the production of nitric oxide. It upregulates the production of inducible nitric oxide synthase (iNOS). This leads to s-nitrosylation of various proteins that prevent the oxidative modification of cysteine residues, thereby reducing the excessive tissue remodeling that leads to IA formation.
In recent years, focus has also been on the noninvasive imaging of inflammation within the IA wall that may help to differentiate the stable IAs from the unstable IAs at a greater risk of rupture. Hasan et al., reported on the use of ferumoxytol-enhanced magnetic resonance imaging (MRI) to image inflammation within the aneurysmal wall. Ferumoxytol is an iron-oxide, macrophage-selective nanoparticle and is cleared by the reticuloendothelial system macrophages. It has been used in MRI studies for cardiovascular imaging, endoleak detection in patients with aortic stent grafts, depiction of deep vein thrombosis, tumor progression, and cancer staging. The findings of these studies suggest that the early uptake of ferumoxytol on MRI indicates an active inflammatory process. These aneurysms are prone to rupture and warrant an early intervention to secure them.
These exciting new findings have also led to the identification of new potential targets for the pharmacological management of IAs. The role of aspirin as a candidate for pharmacotherapy of IAs is being investigated. Depending on the dose, aspirin can inhibit several inflammatory mediators via its irreversible inhibition of cyclooxygenase-2. In the International Study of Unruptured Intracranial Aneurysms (ISUIA), patients with a history of aspirin usage 3 times weekly or greater, had a lower risk of IA rupture and subarachnoid hemorrhage than those who never used aspirin. A clinical trial assessing the role of aspirin in human IAs has recently completed recruitment of subjects, the results of which are yet to be published. (https://clinicaltrials.gov/ct2/show/NCT01710072).
To conclude, inflammation plays a pivotal role in the pathogenesis of IA. Further studies are needed to understand the inflammatory cascade and develop potential targets for pharmacological therapy.
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