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Uterine stress is associated with an increased risk of later life metabolic diseases. In this study, we investigated the effect of diesel exhaust (DE) exposure in utero on adult susceptibility to atherosclerosis in genetically hyperlipidemic mice. Pregnant apolipoprotein E-deficient mice received either DE exposure (~250–300 μg/m3 PM2.5 for 6 h/day, 5 days/week) or filtered air (FA) throughout gestation. Treatment effects on litter size and gender distribution were recorded. Plasma cholesterol and triglycerides were measured at 8, 12 and 16 weeks of age. Urinary 8-isoprostane and liver 8-hydroxy-deoxyguanosine levels were measured at killing at 16 weeks of age. Expression of the antioxidant genes heme oxygenase-1 and the glutamate-cysteine ligase modifier and catalytic subunits were measured in the lung, liver and aorta. The average area and frequency of atherosclerotic lesions were measured in the aortic sinus and innominate arteries. There were significantly smaller litters and higher postnatal mortality in the DE-exposed mice. There were no significant differences in plasma lipids or lipoprotein profiles, expression of antioxidant genes or markers of oxidative stress between treatment groups. There were also no significant differences in average atherosclerotic lesion area in the aortic sinus or innominate arteries of the DE and FA groups although there was a higher frequency of lesions in the DE-exposed group. Our study indicates that in utero DE exposure does not influence later life lipoprotein metabolism, redox homeostasis or the risk of developing larger atherosclerotic lesions.

Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post-monocyte recruitment under inflammatory conditions. Using an acute peritonitis model, we identify a significant defect in macrophage proliferation in mice lacking the leukocyte transmembrane protease ADAM17. The defect is associated with decreased levels of macrophage colony-stimulating factor 1 (CSF-1) in the peritoneum and is rescued by intraperitoneal injection of CSF-1. Cell surface CSF-1 (csCSF-1) is one of the substrates of ADAM17. We demonstrate that both infiltrated neutrophils and macrophages are major sources of csCSF-1. Furthermore, acute shedding of csCSF-1 following neutrophil extravasation is associated with elevated expression of iRhom2, a member of the rhomboid-like superfamily, which promotes ADAM17 maturation and trafficking to the neutrophil surface. Accordingly, deletion of hematopoietic iRhom2 is sufficient to prevent csCSF-1 release from neutrophils and macrophages and to prevent macrophage proliferation. In acute inflammation, csCSF-1 release and macrophage proliferation are self-limiting due to transient leukocyte recruitment and temporally restricted csCSF-1 expression. In chronic inflammation, such as atherosclerosis, the ADAM17-mediated lesional macrophage proliferative response is prolonged. Our results demonstrate a novel mechanism whereby ADAM17 promotes macrophage proliferation in states of acute and chronic inflammation.

Objectives. Oxidative stress contributes to Parkinson’s disease (PD) pathophysiology and progression. The objective was to describe central and peripheral metabolites of redox metabolism and to describe correlations between glutathione (Glu) status, age, and disease severity.Methods. 58 otherwise healthy individuals with PD were examined during a single study visit. Descriptive statistics and scatterplots were used to evaluate normality and distribution of this cross-sectional sample. Blood tests and magnetic resonance spectroscopy (MRS) were used to collect biologic data. Spearman’s rank-order correlation coefficients were used to evaluate the strength and direction of the association. The Unified PD Rating Scale (UPDRS) and the Patient-Reported Outcomes in PD (PRO-PD) were used to rate disease severity using regression analysis.Results. Blood measures of Glu decreased with age, although there was no age-related decline in MRS Glu. The lower the blood Glu concentration, the more severe the UPDRS (P=0.02, 95% CI: −13.96, −1.14) and the PRO-PD (P=0.01, 95% CI: −0.83, −0.11) scores.Discussion. These data suggest whole blood Glu may have utility as a biomarker in PD. Future studies should evaluate whether it is a modifiable risk factor for PD progression and whether Glu fortification improves PD outcomes.

The hypothesis that infectious agents are a risk factor for atherosclerosis has implicated multiple viral and bacterial pathogens in contributing either directly or indirectly to disease progression (Rosenfeld and Campbell, 2011). One of the most vigorously studied organisms has been Chlamydia pneumoniae, which has been associated with cardiovascular disease by seroepidemiological studies, detection of the organism by multiple methods in atherosclerotic tissue, and experimental studies demonstrating biological plausibility. Significantly, C. pneumoniae accelerates lesion progression in mouse and rabbit models of atherosclerosis (Muhlestein et al., 1998; Hu et al., 1999; Moazed et al., 1999; Fong, 2000; Blessing et al., 2001). Early small clinical trials determined whether treatment with macrolides (Azithromycin, Roxithromycin, and Clarithromycin) would be efficacious in secondary prevention of coronary heart disease. These studies yielded mixed results and had several limitations including the small numbers of patients and short duration of treatment and follow-up period (Grayston, 2003). However, half of them demonstrated some beneficial effects, which provided enthusiasm for the potential of antibiotic intervention in coronary artery disease. There have since been four large clinical trials collectively enrolling over 20,000 patients with stable coronary artery disease (WIZARD, ACES, and CLARICOR) or acute coronary syndrome (PROVE-IT–TIMI) (O'Connor et al., 2003; Cannon et al., 2005; Grayston et al., 2005; Jespersen et al., 2006). As there were short term beneficial effects in the WIZARD trial following a 3 month course of Azithromycin, two subsequent studies addressed whether longer term treatment would be efficacious in reducing coronary events. In the ACES study, patients were treated with Azithromycin for 1 year and followed for 46.8 months (Grayston et al., 2005). The PROVE IT-TIMI trial treated with gatifloxacin for a mean duration of 2 years (Cannon et al., 2005). Overall, none of these well-designed trials demonstrated any long term benefit of antibiotic treatment. Furthermore, two large scale trials subsequently found that treatment with either roxithromycin or rifalizil (PROVIDENCE-1) had no beneficial effects in patients with peripheral artery disease (Joensen et al., 2008; Jaff et al., 2009). Cumulatively, these trials clearly demonstrated that anti-chlamydial antibiotics should not be recommended for treatment of patients with coronary heart disease or peripheral artery disease. Prior to the completion of the PROVE-IT and ACES trials, Grayston commented that if the trials demonstrated a beneficial effect of antibiotics, this would provide additional evidence for a role of C. pneumoniae in pathogenesis, but would not prove causality (Grayston, 2003). Alternatively, he predicted that negative results would mostly likely dampen interest in the association of C. pneumoniae and atherosclerosis, but noted that failure of the clinical trials would not rule out a pathogenic role (Grayston, 2003). Indeed, the negative outcome led some to conclude that this proved that C. pneumoniae did not play a role in the pathogenesis of atherosclerosis (Danesh, 2005) and diminished interest in infectious agents as contributing factors for cardiovascular disease (Epstein et al., 2009).

It is now widely accepted that the development of atherosclerotic lesions involves a chronic inflammatory response that includes both innate and adaptive immune mechanisms. However, it is still unclear precisely what induces the inflammatory response. Furthermore, inflammation within the blood vessel can be divided into direct mechanisms where the primary inflammatory events occur within the intima of the blood vessel and contribute to both the initiation and progression of the plaques and indirect mechanisms where inflammation at non-vascular sites can contribute to the progression of the lesions. The direct mechanisms include lipid deposition and modification, influx of lipoprotein associated factors and microparticles derived from many different cell types, and possibly bacterial and viral infection of vascular cells. Indirect mechanisms derive from inflammation related to autoimmune diseases, smoking, respiratory infection, and pollution exposure, and possibly periodontal disease and gastric infection. The mechanisms include secretion of cytokines and other inflammatory factors into the circulation with subsequent uptake into the plaques, egress and recruitment of activated inflammatory cells, formation of dysfunctional HDL and cross reactive autoantibodies.

The Editor’s pick for the June 2006 issue of Arteriosclerosis, Thrombosis, and Vascular Biology was the article by Sasaki et al1 entitled “A Simple Method of Plaque Rupture Induction in Apolipoprotein E–Deficient Mice.” The key term in this title is “plaque rupture.” The article was accompanied by a supportive editorial by Jackson.2 We would like to suggest that the enthusiasm for this experiment as a model for plaque rupture needs to be moderated by a better understanding of the model itself and of human plaque rupture. In 1997, Lindner and coworkers described that flow cessation induced by ligation of the common carotid artery (CCA) near its bifurcation led to constrictive vascular remodeling and neointima formation in mice within 4 weeks.3,4 Flow cessation was followed by loss of medial smooth muscle cells and early recruitment of leukocytes that infiltrated the developing neointima, media, and adventitia during the first week. Focal …

It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can give rise to foam cells, the key component of the fatty streak lesion of atherosclerosis. Oxidation of LDL probably generates a broad spectrum of conjugates between fragments of oxidized fatty acids and apolipoprotein B. We now present three mutually supportive lines of evidence for oxidation of LDL in vivo: (i) Antibodies against oxidized LDL, malondialdehyde-lysine, or 4-hydroxynonenal-lysine recognize materials in the atherosclerotic lesions of LDL receptor-deficient rabbits; (ii) LDL gently extracted from lesions of these rabbits is recognized by an antiserum against malondialdehyde-conjugated LDL; (iii) autoantibodies against malondialdehyde-LDL (titers from 512 to greater than 4096) can be demonstrated in rabbit and human sera.