Abstract
Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU−/−) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by a decline in lung function, destruction of lung architecture, deteriorating gas exchange, and increasingly non-elastic lungs
IHC analysis followed by quantification of intracellular Clusterin staining indicated a loss of intracellular Clusterin protein in IPF compared with Normal and COPD airway epithelial cells (Fig. 1K)
These results suggested that secreted Clusterin was increased and epithelial cell-associated Clusterin was decreased in IPF
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by a decline in lung function, destruction of lung architecture, deteriorating gas exchange, and increasingly non-elastic lungs. The etiology of IPF remains elusive, genotoxic environmental irritants such as cigarette smoke and pollutants contribute to repeated and chronic damage to lung epithelial progenitors and cells[2,3]. Clusterin protein was significantly elevated in circulation but was significantly diminished inside epithelial cells in IPF lungs compared with COPD and normal healthy individuals. Shown is the average Clusterin staining intensity in airway epithelial cells in normal, IPF and COPD lung tissue. Transcriptomic analysis, immunohistochemical (IHC), and flow cytometric analysis of IPF lung showed a loss of expression of Clusterin and components of the Mismatch Repair (MMR), oxidative DNA damage repair and double strand break (DSB) repair pathways in epithelial cells in both the airway and honeycombed regions in IPF lungs. Taken together our data demonstrate that Clusterin regulates DNA repair in response to DNA damaging agents, in which the loss of Clusterin led to chronic DNA damage and the senescence-associated responses in the epithelium potentially predisposing these cells and their progenitors to exhaustion and disrepair
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