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

Journal of Lipid Research

卷:63

Sangmi S. Park¹  Ira J. Goldberg²  Abdoulaye J. Dabo²  Christina W. Agudelo²  Robert F. Foronjy³  Michelle Mai⁴  Matthias Salathe⁴  Roger Alvarez-Buve⁴  Itsaso Garcia-Arcos⁴  Huchong Cai⁴  Jennifer Martinez⁴  Michael D. Kim⁴  Nathalie Baumlin-Schmid⁴  Lillian Chow⁵ 

[1] For correspondence: Itsaso Garcia-Arcos;

[2] Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA;

[3] Department of Medicine, NYU Langone School of Medicine, New York, NY, USA;

[4] Departments of Medicine and Cell Biology, SUNY Downstate Medical Center, New York, NY, USA;

[5] Respiratory Department, Hospital University Arnau de Vilanova and Santa Maria, IRB Lleida, University of Lleida, Lleida, Catalonia, Spain;

关键词: lipoprotein receptors;    cell biology;    ApoE;    receptors;    inflammation;    animal models;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 volume0.05/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.

【 授权许可】

Unknown