Liang Fan, Rashmi S Shetty, Huy Minh Dao, Akarsha Balnadupete, Bharath Somasundram, Ashoka Kumar Bhagavath, Akhila Kongara, Hua Tang, Deborah E Citrin, Robert O Williams, Jay I Peters, Sreerama Shetty
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引用次数: 0
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive and irreversible loss of lung function. CSP7 exerts antifibrotic 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 antifibrotic effects of nintedanib and pirfenidone has not been explored. We compared the effects of oral-gavage-fed standard-of-care antifibrotic 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 (p53fl/fl), microRNA-34a flox (microRNA-34afl/fl), and tamoxifen inducible conditional knockout mice lacking p53 (p53cKO) or microRNA-34a (miR-34acKO) expression in lung fibroblasts. Compared with wild type or p53fl/fl or microRNA-34afl/fl mice, p53cKO and miR-34acKO 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 days 14 and 21 post-bleomycin improved survival, body weight and lung function, combination of CSP7 with nintedanib or pirfenidone was more effective than either drug. Interestingly, p53cKO- and miR-34acKO-PF mice resisted these treatments, supporting the importance of restoration of p53-miR-34a-feedback induction in lung (myo)fibroblasts for the antifibrotic effects.NEW & NOTEWORTHY Pulmonary fibrosis is a progressive and fatal fibroproliferative disease. The current drugs (nintedanib/pirfenidone) only slow clinical progression. Myofibroblasts are the primary effector cells of PF. We found that CSP7, nintedanib and pirfenidone exert antifibrotic effects through restoring p53-microRNA-34a feedback induction in lung (myo)fibroblasts. We further found that daily treatment of mice with CSP7/nintedanib/pirfenidone between days 14 and 21 post-bleomycin lung fibrosis improve survival, body weight and lung function, and combination therapy had added benefit.
期刊介绍:
The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.