The effect of PPE-induced emphysema and chronic LPS-induced pulmonary inflammation on atherosclerosis development in APOE*3-LEIDEN mice

Background: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD). However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the contribution of emphysema in the presence or absence of pulmonary inflammation to the increased risk of CVD, using a mouse model for atherosclerosis. Because smoke is a known risk factor for both COPD and CVD, emphysema was induced by intratracheal instillation of porcine pancreatic elastase (PPE). Methods: Hyperlipidemic APOE*3-Leiden mice were intratracheally instilled with vehicle, 15 or 30 mg PPE and after 4 weeks, mice received a Western-type diet (WTD). To study the effect of emphysema combined with pulmonary inflammation on atherosclerosis, mice received 30 mg PPE and during WTD feeding, mice were intranasally instilled with vehicle or low-dose lipopolysaccharide (LPS; 1 mg/mouse, twice weekly). After 20 weeks WTD, mice were sacrificed and emphysema, pulmonary inflammation and atherosclerosis were analysed. Results: Intratracheal PPE administration resulted in a dose-dependent increase in emphysema, whereas atherosclerotic lesion area was not affected by PPE treatment. Additional low-dose intranasal LPS administration induced a low-grade systemic IL-6 response, as compared to vehicle. Combining intratracheal PPE with intranasal LPS instillation significantly increased the number of pulmonary macrophages and neutrophils. Plasma lipids during the study were not different. LPS instillation caused a limited, but significant increase in the atherosclerotic lesion area. This increase was not further enhanced by PPE. Conclusion: This study shows for the first time that PPE-induced emphysema both in the presence and absence of pulmonary inflammation does not affect atherosclerotic lesion development. © 2013 Khedoe et al

Hepatocyte-specific Inflammation Directly Enhances VLDL-triglyceride Production in Mice

Diabetes mellitus: pathophysiological changes and therap

DELETE LIVER-SPECIFIC IKK-beta ACTIVATION SEVERELY AGGRAVATES ATHEROSCLEROSIS DEVELOPMENT IN APOE*3-LEIDEN MICE

Pathogenesis and treatment of chronic pulmonary disease

Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE * 3-Leiden.CETP mice

Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*. 3 Leiden.CETP (E3L.CETP) mice and adds to the antiatherogenic effect of mild statin treatment, currently the most widely used antiatherogenic therapy. E3L.CETP mice were fed a cholesterol-rich diet without (control) or with resveratrol (0.01% w/w), atorvastatin (0.0027% w/w) or both for 14 weeks. During the study plasma lipid, inflammatory and oxidative stress parameters were determined. Resveratrol reduced atherosclerotic lesion area (-52%) in the aortic root, comparable to atorvastatin (-40%) and the combination of both drugs (-47%). The collagen/macrophage ratio in the atherosclerotic lesion, a marker of plaque stability, was increased by resveratrol (+108%), atorvastatin (+124%) and the combination (+154%). Resveratrol decreased plasma cholesterol levels (-19%) comparable to atorvastatin (-19%) and the combination (-22%), which was completely confined to (very)low-density lipoprotein cholesterol levels in all groups. Post hoc analyses showed that the antiatherogenic effect of atorvastatin could be explained by cholesterol lowering, while the antiatherosclerotic effect of resveratrol could be attributed to factors additional to cholesterol lowering. Markers of inflammation and oxidative stress were not different, but resveratrol improved macrophage function. We conclude that resveratrol potently reduces atherosclerosis development and induces a more stable lesion phenotype in E3L.CETP mice. However, under the experimental conditions tested, resveratrol does not add to the antiatherogenic effect of atorvastatin. © 2013 Elsevier Inc