title: Disruption of pulmonary lipid homeostasis drives cigarette smoke-induced lung inflammation in mice.
abstract: Overwhelming evidence links inflammation to the pathogenesis of smoking-related pulmonary diseases, especially chronic obstructive pulmonary disease (COPD). Despite an increased understanding of the disease pathogenesis, mechanisms initiating smoking-induced inflammatory processes remain incompletely understood. To investigate the mechanisms that initiate and propagate smoke-induced inflammation, we used a well-characterised mouse model of cigarette smoke exposure, mice deficient for interleukin (IL)-1α, IL-1β and Toll-like receptor 4, and antibodies blocking granulocyte-macrophage colony-stimulating factor (GM-CSF). Studies were also pursued using intranasal delivery of human oxidised low-density lipoprotein (hOxLDL), a source of oxidised lipids, to investigate the inflammatory processes associated with impaired lipid homeostasis. We found that cigarette smoke exposure rapidly led to lipid accumulation in pulmonary macrophages, a defining feature of foam cells, which in turn released high levels of IL-1α. In smoke-exposed IL-1α-deficient mice, phospholipids accumulated in the bronchoalveolar lavage, a phenomenon also observed when blocking GM-CSF. Intranasal administration of hOxLDL led to lipid accumulation in macrophages and initiated an inflammatory process that mirrored the characteristics of cigarette smoke-induced inflammation. These findings identify a link between lipid accumulation in macrophages, inflammation and damaged surfactant, suggesting that the response to damaged pulmonary surfactant is a central mechanism that drives cigarette smoke-induced inflammation. Further investigations are required to explore the role of distorted lipid homeostasis in the pathogenesis of COPD.
authors.affiliation: Dept of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
authors.forename: Mathieu C
authors.initials: MC
authors.lastname: Morissette
authors.affiliation: Medical Sciences Graduate Program, McMaster University, Hamilton, ON, Canada.
authors.forename: Pamela
authors.initials: P
authors.lastname: Shen
authors.affiliation: Honours Molecular Biology and Genetics Co-op Program, McMaster University, Hamilton, ON, Canada.
authors.forename: Danya
authors.initials: D
authors.lastname: Thayaparan
authors.affiliation: Dept of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada Dept of Medicine, Firestone Institute of Respiratory Health at St Joseph's Healthcare, McMaster University, Hamilton, ON, Canada stampfli@mcmaster.ca.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stämpfli
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000008:administration & dosage*; D016676:Macrophages, Alveolar / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor