The Effect of PPE-Induced Emphysema and Chronic LPS-Induced Pulmonary Inflammation on Atherosclerosis Development in APOE*3-LEIDEN Mice

Abstract

BackgroundChronic 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).MethodsHyperlipidemic APOE*3-Leiden mice were intratracheally instilled with vehicle, 15 or 30 µg 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 µg PPE and during WTD feeding, mice were intranasally instilled with vehicle or low-dose lipopolysaccharide (LPS; 1 µg/mouse, twice weekly). After 20 weeks WTD, mice were sacrificed and emphysema, pulmonary inflammation and atherosclerosis were analysed.ResultsIntratracheal 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.ConclusionThis 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.

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“…Furthermore, there were no noticeable emphysematous changes or abnormalities in the alveolar spaces or alveolar wall thickness in any of the groups. LPS challenge has been previously used to induce a chronic obstructive pulmonary disease-like phenotype in mice, but these studies have been conducted primarily with endotracheal LPS at a dose greater than used in these experiments (49).…”

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“…The animals were housed in a temperature- and humidity-controlled room with free access to water and standard laboratory food. Mouse pulmonary emphysema was induced by one-time intratracheal administration of 15 μg of porcine pancreatic elastase (PPE) (E788, Sigma-Aldrich, St. Louis, MO, USA) in 50 μL of phosphate-buffered saline (PBS) while control mice received 50 μL of sterile PBS [ 17 ]. After 3 weeks of intratracheal instillation, animals were euthanized.…”

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“…Typically this involves injecting LPS at the site of interest for such diseases. Examples of the use of endotoxin in this way include pre‐eclampsia (Cotechini et al ., ; Faas et al ., ; Faas et al ., ; Lin et al ., ; Liu et al ., ; Rademacher, Gumaa & Scioscia, ; Sakawi et al ., ; Williamson et al ., ; Xue et al ., ), Alzheimer's (Zhan et al ., , ), Parkinson's (Barnum & Tansey, ; Byler et al ., ; Cunningham et al ., ; He et al ., ; Hoban et al ., ; Hritcu & Ciobica, ; Hritcu et al ., ; Liu & Bing, ; Miller et al ., ; Orr, Rowe & Halliday, ; Santiago et al ., ; Tufekci, Genc & Genc, ; Z. Zhang et al ., ), rheumatoid arthritis (Izui, Eisenberg & Dixon, ; Nemeth et al ., ), atherosclerosis (Khedoe et al ., ), multiple sclerosis (di Penta et al ., ; Nguyen et al ., ), Guillain‐Barré syndrome (Prendergast & Moran, ), sepsis (Lewis, Seymour & Rosengart, ; Remick & Ward, ), and stroke (Becker et al ., ; Doll et al ., ; Shim & Wong, ). This far‐from‐exhaustive list illustrates well the generality of this phenomenon.…”