p53-miR-34a Feedback in Lung Fibroblasts Regulates Antifibrotic Effects of CSP7, Nintedanib and Pirfenidone.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive and irreversible loss of lung function. CSP7 exerts anti-fibrotic effects on fibrotic lung (myo)fibroblasts, which are the primary effector cells in progressive pulmonary fibrosis (PF) via restoring p53-microRNA-34a-feedback induction. However, p53-microRNA-34a's role in the anti-fibrotic effects of Nintedanib and Pirfenidone have not been explored. We compared the effects of oral-gavage-fed standard-of-care anti-fibrotic drugs, Nintedanib or Pirfenidone with CSP7 administered by intraperitoneal injection or via airway by dry powder inhalation against bleomycin induced PF using wild-type, p53 flox (p53^fl/fl), microRNA-34a flox (microRNA-34a^fl/fl) and tamoxifen inducible conditional knockout mice lacking p53 (p53^cKO) or microRNA-34a (miR-34a^cKO) expression in lung fibroblasts. Compared to wild-type or p53^fl/fl or microRNA-34a^fl/fl mice, p53^cKO and miR-34a^cKO mice exhibited more severe post-bleomycin body weight and lung function loss, lower survival, and more extracellular matrix deposition. Although daily treatment of wild-type mice with CSP7 or with Nintedanib or Pirfenidone between day 14-21 post-bleomycin improved survival, body weight and lung function, combination of CSP7 with Nintedanib or Pirfenidone was more effective than either drug. Interestingly, p53^cKO- and miR-34a^cKO-PF mice resisted these treatments, supporting the importance of restoration of p53-miR-34a-feedback induction in lung (myo)fibroblasts for the anti-fibrotic effects.