Editors' ChoiceChronic Lung Disease

Not Just the Heart of the Matter: Cholesterol’s Role in Emphysema

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Science Translational Medicine  18 Apr 2012:
Vol. 4, Issue 130, pp. 130ec68
DOI: 10.1126/scitranslmed.3004137

How broadly does abnormal cholesterol metabolism affect our bodies? Links have emerged between atherosclerosis and chronic lung diseases such as emphysema, which is characterized by alveolar wall destruction, airspace enlargement in the lung, and obstruced airflow during breathing. Both diseases are associated with inflammation, and the risk of both is increased by smoking. Atherosclerosis is a leading cause of death in chronic obstructive pulmonary disease, and individuals with airflow obstruction have a higher atherosclerotic disease burden than those with normal lung function, even when adjusted for smoking. It is not known, however, how high cholesterol levels might affect lung structure independent of smoking.

Goldklang et al. aimed to determine if diet-induced hypercholesterolemia alters lung inflammation and the development of emphysema in two mouse models of atherosclerosis. The mice lacked either apolipoprotein E (ApoE)—a lipid-binding protein that promotes cholesterol efflux from macrophages, accepting cholesterol from cells and delivering it to the liver for excretion—or low-density lipoprotein receptor (LDLR), which mediates the removal of excess circulating LDL cholesterol.

Apoe–/– mice fed a Western-type diet developed airspace enlargement and displayed increased lung inflammation (for example, macrophages and lymphocytes); expression and activity of matrix metalloproteinases, which play a role in the pathogenesis of emphysema; and Toll-like receptor–4 (TLR-4) pathway signaling, which is involved in innate immune system activation. The authors also suggest that emphysema might result from TLR activation caused by abnormal cholesterol efflux, rather than hypercholesterolemia alone. In contrast, Ldlr–/– mice did not exhibit lung inflammation or emphysema, despite having equally high total serum cholesterol.

Thus, this study links abnormal cholesterol metabolism (or transport) with lung inflammation and destruction in the absence of smoke exposure, creating a possible mechanistic link between atherosclerosis and the development of emphysema. Whether this mechanism occurs in humans is unknown but is a promising area for further research. This work has important public health implications, given our aging population and the increasing burden of atherosclerosis and emphysema. What role might diet, serum lipid levels, and the lipid-lowering statin drugs play in mitigating the pathogenesis of diseases such as emphysema?

M. P. Goldklang et al., Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in Apoe-deficient mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 23 March 2012 (10.1152/ajplung.00454.2010). [Full Text]

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