Abstract
Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number of actionable targets whose clinical exploration will help achieve the goal of optimizing beneficial effects while avoiding undue interference with host defenses or other unwanted actions. This review aims to furnish the foundation for this quest by critical evaluation of the current state of anti-inflammatory interventions within close reach of clinical application, with a primary focus on innate immunity. In particular, this paper highlights the pathway from the inflammasome, through interleukin (IL)-1 to IL-6 supported by a promising body of pre-clinical, clinical, and human genetic data. This paper also considers the use of biomarkers to guide allocation of anti-inflammatory therapies as a step toward realizing the promise of precision medicine. The validation of decades of experimental work and association studies in humans by recent clinical investigations provides a strong impetus for further efforts to target inflammation in atherosclerosis to address the considerable risk that remains despite current therapies.
Highlights
The literature abounds with publications on inflammation in atherosclerosis
We demonstrated the flammatory signaling within atheromata, CD40 ligand (CD154), as an activator of the proability of a pro-inflammatory cytokine that we had implicated in inflammatory signaling cessing of pro-IL-1β to the active cytokine in human vascular cells [23]
The inflammatory hypothesis of atherosclerosis in no way conflicted with traditional risk factors
Summary
The literature abounds with publications on inflammation in atherosclerosis. Yet, only a few years ago, this concept met with considerable skepticism in many quarters. Produced by activated T lymphocytes and other adaptive immune cells, IFN-γ signals to many cell types including mononuclear phagocytes, the foot soldiers of the innate immune response. TNF, IFN-γ affects important functions of vascular endothelial and smooth muscle cells along with many other cell types of multiple organs Each member of this cytokine trio can induce the expression of chemokines, protein mediators of directed migration of affects important functions vascular endothelial and and smooth muscle cells various classes of leukocytes [1].of. Effectiveprovide blockadea of major cytokines, particintervention in disease Given their often essential roles in host defenses, cytokine inhiularly those situated proximally in inflammatory pathways, comes with the potential limbitionof can prove a double-edged sword.Examples.
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