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.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by an excessive inflammatory response towards noxious particles and gases, such as cigarette smoke (CS)
To determine the contribution of emphysema alone on atherosclerosis development, E3L mice were intratracheally instilled with vehicle or 15 or 30 mg porcine pancreatic elastase (PPE) after which atherosclerosis was induced by 20 weeks of Western-type diet (WTD) feeding
Intratracheal PPE instillation caused a significant dosedependent increase in emphysema as determined by morphometrical assessment of the mean linear intercept (MLI) (Fig. 1B) and AT ratio (Fig. 1C), indicating destruction of alveolar walls and enlargement of alveolar space
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by an excessive inflammatory response towards noxious particles and gases, such as cigarette smoke (CS). CS is the main trigger that leads to activation of macrophages and epithelial cells, resulting in the recruitment and activation of other (immune) cells, mucus hypersecretion, alveolar wall destruction (emphysema) and airway remodeling [1]. These structural changes in the airways and lung parenchyma cause the chronic progressive airflow obstruction. In addition to these pulmonary manifestations, COPD patients often present with comorbidities such as cardiovascular diseases (CVD) and lung cancer. Because smoke is a known risk factor for both COPD and CVD, emphysema was induced by intratracheal instillation of porcine pancreatic elastase (PPE)
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