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Eur Respir J. 2015 Nov;46(5):1451-60. doi: 10.1183/09031936.00216914. Epub 2015 Jun 25.

Disruption of pulmonary lipid homeostasis drives cigarette smoke-induced lung inflammation in mice.

Author information

1
Dept of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
2
Medical Sciences Graduate Program, McMaster University, Hamilton, ON, Canada.
3
Honours Molecular Biology and Genetics Co-op Program, McMaster University, Hamilton, ON, Canada.
4
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.

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.

PMID:
26113683
DOI:
10.1183/09031936.00216914
[Indexed for MEDLINE]
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