title: Genetic deletion of apolipoprotein A-I increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung.
abstract: 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.
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Sandhya
authors.initials: S
authors.lastname: Nandedkar
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Haiqing
authors.initials: H
authors.lastname: Gao
authors.forename: Thom
authors.initials: T
authors.lastname: Feroah
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.forename: Marie L
authors.initials: ML
authors.lastname: Schulte
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.forename: Jason
authors.initials: J
authors.lastname: Jarzembowski
authors.forename: Mary
authors.initials: M
authors.lastname: Sorci-Thomas
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D008076:Cholesterol, HDL / Q000097:blood; D003094:Collagen / Q000378:metabolism*; D017353:Gene Deletion; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D050356:Lipid Metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D014664:Vasodilation
chemical_list: D016632:Apolipoprotein A-I; D015415:Biomarkers; D008076:Cholesterol, HDL; D003094:Collagen; D043303:Aryldialkylphosphatase