LRP1 loss in airway epithelium exacerbates smoke-induced oxidative damage and airway remodeling.

Autor: Garcia-Arcos I; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA. Electronic address: Itsaso.garcia-arcos@downstate.edu., Park SS; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Mai M; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Alvarez-Buve R; Respiratory Department, Hospital University Arnau de Vilanova and Santa Maria, IRB Lleida, University of Lleida, Lleida, Catalonia, Spain., Chow L; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Cai H; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Baumlin-Schmid N; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA., Agudelo CW; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Martinez J; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Kim MD; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA., Dabo AJ; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA., Salathe M; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA., Goldberg IJ; Department of Medicine, NYU Langone School of Medicine, New York, NY, USA., Foronjy RF; Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA.
Jazyk: angličtina
Zdroj: Journal of lipid research [J Lipid Res] 2022 Apr; Vol. 63 (4), pp. 100185. Date of Electronic Publication: 2022 Feb 21.
DOI: 10.1016/j.jlr.2022.100185
Abstrakt: The LDL receptor-related protein 1 (LRP1) partakes in metabolic and signaling events regulated in a tissue-specific manner. The function of LRP1 in airways has not been studied. We aimed to study the function of LRP1 in smoke-induced disease. We found that bronchial epithelium of patients with chronic obstructive pulmonary disease and airway epithelium of mice exposed to smoke had increased LRP1 expression. We then knocked out LRP1 in human bronchial epithelial cells in vitro and in airway epithelial club cells in mice. In vitro, LRP1 knockdown decreased cell migration and increased transforming growth factor β activation. Tamoxifen-inducible airway-specific LRP1 knockout mice (club Lrp1 -/- ) induced after complete lung development had increased inflammation in the bronchoalveolar space and lung parenchyma at baseline. After 6 months of smoke exposure, club Lrp1 -/- mice showed a combined restrictive and obstructive phenotype, with lower compliance, inspiratory capacity, and forced expiratory volume 0.05 /forced vital capacity than WT smoke-exposed mice. This was associated with increased values of Ashcroft fibrotic index. Proteomic analysis of room air exposed-club Lrp1 -/- mice showed significantly decreased levels of proteins involved in cytoskeleton signaling and xenobiotic detoxification as well as decreased levels of glutathione. The proteome fingerprint created by smoke eclipsed many of the original differences, but club Lrp1 -/- mice continued to have decreased lung glutathione levels and increased protein oxidative damage and airway cell proliferation. Therefore, LRP1 deficiency leads to greater lung inflammation and damage and exacerbates smoke-induced lung disease.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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