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Grant Abstract: Effects of fish oil on inflammation and vascular function in claudicants

Grant Number: 5K23HL122446-03
PI Name: Grenon
Project Title: Effects of fish oil on inflammation and vascular function in claudicants

Abstract: Peripheral arterial disease (PAD) is estimated to occur in 6% of people older than 40 years, corresponding to 7.2 million affected individuals in the United States alone. Atherosclerotic lesions, the hallmark of PAD, represent a series of highly specific cellular and molecular responses that can best be described, in aggregate, as an inflammatory disease. This disease state begins from a pure inflammatory lesion, known as the fatty streak, which forms from peripheral blood mononuclear cells (PBMCs) such as monocytes and T lymphocytes, and can progress to occlusive lesions causing significant morbidity, limb loss, and death. The resolution of inflammation had long been thought of as a passive process involving the dilution of inflammatory mediators. However, recent work has demonstrated that the process of resolution is actually an active, programmed response. Omega-3 polyunsaturated fatty acids (n-3 PUFA), such as those found in fish oils, are used by a diverse array of cells including PBMCs to derive structurally distinct families of signaling molecules collectively termed specialized pro-resolving mediators (SPMs). Recent work has demonstrated direct beneficial effects of SPMs and their precursors in different disease processes including inflammatory diseases. Further, our group has demonstrated that short-term intensive dose fish oil supplementation increases biochemical SPM pathways in PAD patients. The overall goal of this research program is to determine if targeting inflammation and its resolution can improve outcomes in PAD. This proposal will examine if a nutritional intervention can modulate the acute inflammatory response, and promote resolution, in PAD patients through the action of PBMCs. The central hypothesis is that high-dose, short-term n-3 PUFA oral supplementation will reduce PBMC derived inflammation and will promote PBMC derived resolution in PAD. This proposal capitalizes on an established translational science infrastructure for conducting human research in PAD and vascular inflammation to test this hypothesis via the following specific aims: (1) Determine if high-dose n-3 PUFA supplementation modulates PBMC inflammatory phenotype in PAD patients and (2) Determine if high-dose n-3 PUFA supplementation induces a “pro-resolving” phenotype in PAD patients. The significance of this research is that it will lead to a better understanding of the inflammatory response affecting patients with PAD, which may lead to novel therapeutic strategies to improve the management of vascular disease.

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