title: The effect of PPE-induced emphysema and chronic LPS-induced pulmonary inflammation on atherosclerosis development in APOE*3-LEIDEN mice.
abstract: 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 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P Padmini S J
authors.initials: PP
authors.lastname: Khedoe
authors.forename: Man C
authors.initials: MC
authors.lastname: Wong
authors.forename: Gerry T M
authors.initials: GT
authors.lastname: Wagenaar
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
authors.forename: Miranda
authors.initials: M
authors.lastname: van Eck
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000097:blood; D008055:Lipids / Q000097:blood; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D008822:Mice, Transgenic; D010196:Pancreatic Elastase / Q000009:adverse effects; D011014:Pneumonia / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000150:complications* / Q000473:pathology
chemical_list: D053318:Apolipoprotein E3; D018836:Inflammation Mediators; D008055:Lipids; D008070:Lipopolysaccharides; C052720:apolipoprotein E3 (Leidein); D010196:Pancreatic Elastase