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Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. J Lipid Res 2010 Sep;51(9):2560-70



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Scopus ID

2-s2.0-77956861083   63 Citations


The relationship between high-density lipoprotein and pulmonary function is unclear. To determine mechanistic relationships we investigated the effects of genetic deletion of apolipoprotein A-I (apoA-I) on plasma lipids, paraoxonase (PON1), pro-inflammatory HDL (p-HDL), vasodilatation, airway hyperresponsiveness and pulmonary oxidative stress, and inflammation. ApoA-I null (apoA-I(-/-)) mice had reduced total and HDL cholesterol but increased pro-inflammatory HDL compared with C57BL/6J mice. Although PON1 protein was increased in apoA-I(-/-) mice, PON1 activity was decreased. ApoA-I deficiency did not alter vasodilatation of facialis arteries, but it did alter relaxation responses of pulmonary arteries. Central airway resistance was unaltered. However, airway resistance mediated by tissue dampening and elastance were increased in apoA-I(-/-) mice, a finding also confirmed by positive end-expiratory pressure (PEEP) studies. Inflammatory cells, collagen deposition, 3-nitrotyrosine, and 4-hydroxy-2-nonenal were increased in apoA-I(-/-) lungs but not oxidized phospholipids. Colocalization of 4-hydroxy-2-nonenal with transforming growth factor beta-1 (TGFbeta-1 was increased in apoA-I(-/-) lungs. Xanthine oxidase, myeloperoxidase and endothelial nitric oxide synthase were increased in apoA-I(-/-) lungs. Dichlorodihydrofluorescein-detectable oxidants were increased in bronchoalveolar lavage fluid (BALF) in apoA-I(-/-) mice. In contrast, BALF nitrite+nitrate levels were decreased in apoA-I(-/-) mice. These data demonstrate that apoA-I plays important roles in limiting pulmonary inflammation and oxidative stress, which if not prevented, will decrease pulmonary artery vasodilatation and increase airway hyperresponsiveness.

Author List

Wang W, Xu H, Shi Y, Nandedkar S, Zhang H, Gao H, Feroah T, Weihrauch D, Schulte ML, Jones DW, Jarzembowski J, Sorci-Thomas M, Pritchard KA Jr


Jason A. Jarzembowski MD, PhD Sr Associate Dean, CEO CSG, Professor in the Pathology department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Research Scientist II in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Apolipoprotein A-I
Bronchial Hyperreactivity
Bronchoalveolar Lavage Fluid
Cholesterol, HDL
Gene Deletion
Lipid Metabolism
Mice, Inbred C57BL
Oxidative Stress