Inflammatory Mediators in Vascular Disease: Identifying Promising Targets for Intracranial Aneurysm Research

Inflammatory processes are implicated in many diseases of the vasculature and have been shown to play a key role in the formation of intracranial aneurysms (IAs). Although the specific mechanisms underlying these processes have been thoroughly investigated in related pathologies, such as atherosclerosis, there remains a paucity of information regarding the immunopathology of IA. Cells such as macrophages and lymphocytes and their effector molecules have been suggested to be players in IA, but their specific interactions and the role of other components of the inflammatory response have yet to be determined. Drawing parallels between the pathogenesis of IA and other vascular disorders could provide a roadmap for developing a mechanistic understanding of the immunopathology of IA and uncovering useful targets for therapeutic intervention. Future research should address the presence and function of leukocyte subsets, mechanisms of leukocyte recruitment and activation, and the role of damage-associated molecular patterns in IA

Is the Broad-Line Region Clumped or Smooth? Constraints from the H alpha Profile in NGC 4395, the Least Luminous Seyfert 1 Galaxy

The origin and configuration of the gas which emits broad lines in Type I active galactic nuclei is not established yet. The lack of small-scale structure in the broad emission-line profiles is consistent with a smooth gas flow, or a clumped flow with many small clouds. An attractive possibility for the origin of many small clouds is the atmospheres of bloated stars, an origin which also provides a natural mechanism for the cloud confinement. Earlier studies of the broad-line profiles have already put strong lower limits on the minimum number of such stars, but these limits are sensitive to the assumed width of the lines produced by each cloud. Here we revisit this problem using high-resolution Keck spectra of the H alpha line in NGC 4395, which has the smallest known broad-line region (~10^14 cm). Only a handful of the required bloated stars (each having r~10^14 cm) could fit into the broad-line region of NGC 4395, yet the observed smoothness of the H alpha line implies a lower limit of ~10^4-10^5 on the number of discrete clouds. This rules out conclusively the bloated-stars scenario, regardless of any plausible line-broadening mechanisms. The upper limit on the size of the clouds is ~10^12 cm, which is comparable to the size implied by photoionization models. This strongly suggests that gas in the broad-line region is structured as a smooth rather than a clumped flow, most likely in a rotationally dominated thick disk-like configuration. However, it remains to be clarified why such a smooth, gravity-dominated flow generates double-peaked emission lines only in a small fraction of active galactic nuclei.Comment: 12 pages, including 3 figures, accepted for publication in The Astrophysical Journa

A Comprehensive Review of the Superficial Anterior Atlanto-Occipital Ligament of the Craniocervical Junction

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Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture. APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs. CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies