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

Itsaso Garcia-Arcos,Sangmi S Park,Michelle Mai,Roger Alvarez-Buve,Lillian Chow,Huchong Cai,Nathalie Baumlin-Schmid,Christina W Agudelo,Jennifer Martinez,Michael D Kim,Abdoulaye J Dabo,Matthias Salathe,Ira J Goldberg,Robert F Foronjy

doi:10.1016/j.jlr.2022.100185

Abstract

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.

Highlights

Supplementary key words lipoprotein receptors cell biology ApoE receptors inflammation animal models epithelial cells lung disease
We found that LDL receptor-related protein 1 (LRP1) expression was increased primarily in bronchial epithelium of chronic obstructive pulmonary disease (COPD) patients and generated club cell-specific tamoxifeninducible LRP1 knockout mice
LRP1 showed positive staining in cells in the airway epithelium and parenchyma (Fig. 1A). quantitative PCR (qPCR) of isolated club cells, which in mice, line the bronchi and distal airways together with ciliated cells, showed higher LRP1 expression in mice exposed to 6 months of secondhand smoke than in mice exposed to room air (P < 0.05; Fig. 1A)

Summary

Introduction

Some of the functions of LRP1 reflect its role as a lipoprotein receptor, whereas others are more in line with its anti-inflammatory actions mediated by interaction with serpins and tissue inhibitor of metalloproteinases [4, 5]. Genome-wide association study has linked SNPs in LRP1 with several diseases, such as abdominal aortic aneurysm, hyperlipidemia, and chronic obstructive pulmonary disease (COPD) [6–9]. Some of these SNPs decrease the mRNA stability and protein expression of LRP1. These data suggest that anti-inflammatory roles of LRP1 in macrophages are predominant over its lipid metabolic effects. Liver-specific Lrp knockout mice developed nonalcoholic fatty liver disease [14], an effect opposite to that expected for a receptor known to mediate uptake of chylomicron remnants.

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