Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broadspectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1-and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1-and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1-and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine-induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.

Wound healing is a multistep process with four overlapping but distinct stages: hemostasis, inflammation, proliferation, and remodeling. An alteration at any stage may lead to the development of chronic non-healing wounds or excessive scar formation. Impaired wound healing presents a significant health and economic burden to millions of individuals worldwide, with diabetes mellitus and aging being major risk factors. Ongoing understanding of the mechanisms that underly wound healing is required for the development of new and improved therapies that increase repair. Chemokines are key regulators of the wound healing process. They are involved in the promotion and inhibition of angiogenesis and the recruitment of inflammatory cells, which release growth factors and cytokines to facilitate the wound healing process. Preclinical research studies in mice show that the administration of CCL2, CCL21, CXCL12, and a CXCR4 antagonist as well as broad-spectrum inhibition of the CC-chemokine class improve the wound healing process. The focus of this review is to highlight the contributions of chemokines during each stage of wound healing and to discuss the related molecular pathologies in complex and chronic non-healing wounds. We explore the therapeutic potential of targeting chemokines as a novel approach to overcome the debilitating effects of impaired wound healing.

Objective-Microparticles of iron oxide (MPIO) distort magnetic field creating marked contrast effects far exceeding their physical size. We hypothesized that antibody-conjugated MPIO would enable magnetic resonance imaging (MRI) of endothelial cell adhesion molecules in mouse atherosclerosis. Methods and Results-MPIO (4.5 m) were conjugated to monoclonal antibodies against vascular cell adhesion molecule-1 (VCAM-MPIO) or P-selectin (P-selectin-MPIO). In vitro, VCAM-MPIO bound, in dose-dependent manner, to tumor necrosis factor (TNF)-␣ stimulated sEND-1 endothelial cells, as quantified by light microscopy (R 2 ϭ0.94, Pϭ0.03) and by MRI (R 2 ϭ0.98, Pϭ0.01). VCAM-MPIO binding was blocked by preincubation with soluble VCAM-1. To mimic leukocyte binding, MPIO targeting both VCAM-1 and P-selectin were administered in apolipoprotein E Ϫ/Ϫ mice. By light microscopy, dual-targeted MPIO binding to endothelium overlying aortic root atherosclerosis was 5-to 7-fold more than P-selectin-MPIO (PϽ0.05) or VCAM-MPIO (PϽ0.01) alone. Dual-targeted MPIO, injected intravenously in vivo bound aortic root endothelium and were quantifiable by MRI ex vivo (3.5-fold increase versus control; PϽ0.01). MPIO were well-tolerated in vivo, with sequestration in the spleen after 24 hours. Conclusions-Dual-ligand MPIO bound to endothelium over atherosclerosis in vivo, under flow conditions. MPIO may provide a functional MRI probe for detecting endothelial-specific markers in a range of vascular pathologies. Key Words: microparticles of iron oxide Ⅲ atherosclerosis Ⅲ magnetic resonance imaging Ⅲ molecular imaging M agnetic resonance imaging (MRI) has demonstrated substantial utility in phenotyping vascular disease. Using inherent physico-chemical properties that confer particular tissue relaxivities, it has been possible to characterize the vessel wall in atherosclerosis at a submillimeter level. 1,2 However, to capitalize fully on the diagnostic potential of MRI requires imaging at molecular and cellular levels. [3][4][5][6][7][8][9] To achieve this, purpose-built contrast agents are needed that can identify molecules of interest with high specificity, while conveying sufficient contrast to be easily distinguished from unenhanced tissue.Specificity can be achieved through conjugation of contrast agent with monoclonal antibodies or their immunospecific fragments F(ab), peptides, or peptide-mimetics. Previous approaches have included integrin-conjugated gadolinium-rich perfluorocarbon nanoparticles, 10 peptide-conjugated nanoparticles of iron oxide, 11 and fibrin-specific cyclic peptide labeled with gadolinium. 12 Gadolinium-based contrast agents shorten T1 providing positive contrast on T1-weighted images. However, for the quantities that can be delivered to an endothelial monolayer, the contrast effects are relatively modest. By comparison, iron oxide nanoparticles provide greater contrast effects, but require many particles to be delivered to a given voxel. Another potential drawback is that contrast effects are manifest in T 2 *-weighted images...

Population studies have shown that plasma HDL levels correlate inversely with cardiovascular disease risk. In recent years there has been intense interest in developing strategies for exploiting these cardioprotective properties by increasing HDL levels. While this approach has considerable merit, it is important to recognize that HDL are structurally and functionally diverse and consist of numerous, highly dynamic subpopulations of particles that do not all inhibit atherosclerosis to the same extent. For this reason it is essential to assess HDL subpopulation distribution and functionality when considering therapeutic interventions that raise HDL levels. This review documents what is known about the relationship between the metabolism and function of HDL subpopulations and how this affects their cardioprotective properties.-Rye, K-A., C. A. Bursill, G. Lambert, F. Tabet, and P. J. Barter. The metabolism and anti-atherogenic properties of HDL. J. Lipid Res. 2009. 50: S195-S200.Supplementary key words HDL remodelling • HDL subpopulations • HDL function HDL, the smallest and most dense of all plasma lipoproteins, consist of several distinct subpopulations of particles that vary in size, shape, density, surface charge, and composition. An inverse relationship between HDL levels and premature cardiovascular disease has been observed in many large-scale prospective studies (1, 2). This relationship is also evident in animal studies (3,4).HDL have several potentially anti-atherogenic properties. The best known of these is their ability to remove cholesterol from cells, such as macrophages in the artery wall, in the first step of the reverse cholesterol transport pathway (5). HDL also inhibit LDL oxidation (6), promote endothelial repair (7), improve endothelial function (8), have anti-thrombotic and anti-inflammatory properties (8, 9), and inhibit the binding of monocytes to the endothelium (10). In addition to preventing atherosclerotic lesion progression, HDL also promote lesion regression in animals (11, 12).This review presents evidence that several of the aforementioned anti-atherogenic functions of HDL are mediated by specific subpopulations of particles. To appreciate this functional diversity, it is important to understand something of the origins and heterogeneity of HDL subpopulations. ORIGINS OF HDLHDL originate as discoidal particles that are either secreted from the liver or assembled in the plasma from the individual constituents. Discoidal HDL consist of two or more apolipoprotein molecules complexed with phospholipids and unesterified cholesterol (Fig. 1A). These particles are excellent substrates for LCAT, the enzyme that generates most of the cholesteryl esters in plasma (13). Cholesteryl esters are extremely hydrophobic and partition into the center of the particles as they are formed. This converts discoidal HDL into the large spherical HDL particles that predominate in normal human plasma. It also depletes the HDL surface of cholesterol and establishes a concentration gradient down which ...