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Loss of ABCG1 Results in Chronic Pulmonary Inflammation¹

Ángel Baldán^*,, Aldrin V. Gomes^,, Peipei Ping^, and Peter A. Edwards^2,*,,

^* Department of Biological Chemistry, Center for Health Sciences, David Geffen School of Medicine, Department of Medicine, Department of Physiology, and Molecular Biology Institute, University of California, Los Angeles, CA 90095

ABCG1, a member of the ATP-binding cassette transporter superfamily, is highly expressed in multiple cells of the lung. Loss of ABCG1 results in severe pulmonary lipidosis in mice, with massive deposition of cholesterol in both alveolar macrophages and type 2 cells and the accumulation of excessive surfactant phospholipids. These observations are consistent with ABCG1 controlling cellular sterol metabolism. Herein, we report on the progressive and chronic inflammatory process that accompanies the lipidosis in the lungs of Abcg1^–/– mice. Compared with wild-type animals, the lungs of aged chow-fed mice deficient in ABCG1 show distinctive signs of inflammation that include macrophage accumulation, lymphocytic infiltration, hemorrhage, eosinophilic crystals, and elevated levels of numerous cytokines and cytokine receptors. Analysis of bronchoalveolar lavages obtained from Abcg1^–/– mice revealed elevated numbers of foamy macrophages and leukocytes and the presence of multiple markers of inflammation including crystals of chitinase-3-like proteins. These data suggest that cholesterol and/or cholesterol metabolites that accumulate in Abcg1^–/– lungs can trigger inflammatory signaling pathways. Consistent with this hypothesis, the expression of a number of cytokines was found to be significantly increased following increased cholesterol delivery to either primary peritoneal macrophages or Raw264.7 cells. Finally, cholesterol loading of primary mouse macrophages induced cytokine mRNAs to higher levels in Abcg1^–/–, as compared with wild-type cells. These results demonstrate that ABCG1 plays critical roles in pulmonary homeostasis, balancing both lipid/cholesterol metabolism and inflammatory responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants 30568 and 68445 (to P.A.E.), a grant from the Laubisch Fund (to P.A.E.), and a grant from Pfizer, Inc. (to P.A.E.). Á.B. was partially supported by an American Heart Association (Western Affiliate) Postdoctoral Fellowship (0525010Y).

² Address correspondence and reprint requests to Dr. Peter A. Edwards, University of California-Los Angeles, Department of Biological Chemistry, 615 Charles E. Young Drive South, Box 951737, BSRB, Los Angeles, CA 90095. E-mail address: pedwards{at}mednet.ucla.edu

³ Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; ABC, ATP-binding cassette; LDL, low density lipoprotein; RT-qPCR, real time quantitative PCR; BAL, bronchoalveolar lavage; HF/HC, high fat/high cholesterol; MMP, matrix metalloproteinases; LXR, liver X receptor; HDL, high density lipoprotein; TIMP, tissue inhibitors of matrix metalloproteinases; ACAT, acyl-coenzymeA:cholesterol acyltransferase.