p53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. The pathogenesis of interstitial lung diseases, including its most common form, IPF, remains poorly understood. Alveolar epithelial cell (AEC) apoptosis, proliferation, and accumulation of myofibroblasts and extracellular matrix deposition results in progressive loss of lung function in IPF. We found induction of tumor suppressor protein, p53, and apoptosis with suppression of urokinase-type plasminogen activator (uPA) and the uPA receptor in AECs from the lungs of IPF patients, and in mice with bleomycin, cigarette smoke, silica, or sepsis-induced lung injury. Treatment with the caveolin-1 scaffolding domain peptide (CSP) reversed these effects. Consistent with induction of p53, AECs from IPF lungs or mice with diverse types of lung injuries showed increased p53 acetylation and miR-34a expression with reduction in Sirt1. This was significantly reduced after treatment of wild-type mice with CSP, and uPA-deficient mice were unresponsive. Bleomycin failed to induce miR-34a in p53- or plasminogen activator inhibitor-1 (PAI-1)-deficient mice. CSP-mediated inhibition of miR-34a restored Sirt1, suppressed p53 acetylation and apoptosis in injured AECs, and prevented pulmonary fibrosis (PF). AEC-specific suppression of miR-34a inhibited bleomycin-induced p53, PAI-1, and apoptosis and prevented PF, whereas overexpression of precursor-miR-34a increased p53, PAI-1, and apoptosis in AECs of mice unexposed to bleomycin. Our study validates p53-miR-34a feedback as a potential therapeutic target in PF.

Anticancer Drug-Induced Epithelial-Mesenchymal Transition via p53/miR-34a axis in A549/ABCA3 Cells

“…Thus, the present study would provide new findings concerning the relationship between drug-induced EMT and miR-34a in alveolar epithelial cells. On one hand, it has been reported that miR-34a enhanced alveolar epithelial cell apoptosis and promoted BLM-induced pulmonary fibrosis in mice (33). Furthermore, we found that miR-34a mimic introduction increased mRNA expression level of COL1A1 and fibronectin in A549/ABCA3 cells, which are critical extracellular matrix components in pulmonary fibrosis, indicating that miR-34a may contribute to the development of pulmonary fibrosis.…”

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis

“…The tumor suppressor protein p53 induces cell cycle arrest, apoptosis, senescence, and innate immunity. Induction of p53 is associated with lung injury and development of pulmonary fibrosis (33)(34)(35). Type II alveolar epithelial cell (AEC II) apoptosis is associated with acute lung injury and the development of pulmonary fibrosis.…”

“…Type II alveolar epithelial cell (AEC II) apoptosis is associated with acute lung injury and the development of pulmonary fibrosis. Active induction of p53 and apoptosis are found in AEC II from IPF patients (35). Lung injury due to exposure to DNA-damaging agents like bleomycin rapidly induces p53 expression in AEC II (34).…”

p53 Expression in Lung Fibroblasts Is Linked to Mitigation of Fibrotic Lung Remodeling

“…40,41 Increased p53 contributes to AEC apoptosis, which leads to development of PF, and suppression of excessive p53 inhibits AEC apoptosis and prevents PF. 35,41 Chronic lung epithelial injury initiates PF and can be prevented by inhibiting AEC apoptosis through control of excessive p53. 35 However, fLfs populate, continue to expand, and replace epithelial cells in the fibrotic foci of IPF lungs, leading to progressive destruction of lung architecture and loss of lung function.…”