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The role of surfactant protein d in atherosclerosis

University of British Columbia

Elevated concentrations of surfactant protein D (SP-D) in the serum have been associated with cardiovascular disease (CVD) mortality. It is not known, however, whether this relationship is causal or an epiphenomenon of lung disease or inflammation. The primary purpose of this thesis was to investigate the effects of SP-D on atherosclerosis. The overarching hypothesis driving this study is that SP-D is pro-atherogenic by modulating plasma lipids and systemic inflammation. These studies will enable development of SP-D as a biomarker of atherosclerosis, ischemic heart disease, and stroke and determine whether SP-D can be a therapeutic target to reduce CVD. To address the hypothesis, SP-D-knockout (KO) mice were crossed with apolipoprotein E (ApoE)-KO mice to produce mice deficient in both SP-D and ApoE. These mice were fed a high fat diet (HFD) for twelve weeks. We then measured the size of atherosclerotic lesions in aorta, determined the lipid profile in the serum, and measured circulating inflammatory cytokines and white blood cell counts in mice. We also challenged SP-D-deficient mice with lipopolysaccharide (LPS), which was microsprayed directly into the trachea. We then determined endothelial function of the descending aorta, 24 hours after the LPS challenge. We found that in the atherosclerotic plaque was significantly smaller in ApoE-KO mice lacking SP-D compared with apoE mice with intact SP-D. Absence of SP-D in the apo-E KO mice resulted in reduced levels of low density lipoprotein (LDL) cholesterol and total cholesterols, and a marked attenuation of certain parameters of systemic inflammation including neutrophil to lymphocyte ratios (NLR) and interleukin (IL)-6 in serum. Deficiency of SP-D was also associated with improved endothelial function following intratracheal LPS challenge. Together, these findings indicate that SP-D plays an active role in modulating lipid profile and systemic inflammation and most importantly may enhance atherosclerosis and thus contribute directly to excess cardiovascular morbidity and mortality.

Text

2013-08-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44734

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/