Abstract
Impaired apoptotic clearance of myofibroblasts can result in the continuous expansion of scar tissue during the persistent injury in the lung. However, the molecular and cellular mechanisms underlying the apoptotic clearance of multiple mesenchymal cells including fibrocytes, fibroblasts and myofibroblasts in severe fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) remain largely unknown. We analyzed the apoptotic pathways activated in mesenchymal cells of IPF and in a mouse model of TGFα-induced pulmonary fibrosis. We found that fibrocytes and myofibroblasts in fibrotic lung lesions have acquired resistance to Fas-induced apoptosis, and an FDA-approved anti-fibrotic agent, nintedanib, effectively induced apoptotic cell death in both. In support, comparative gene expression analyses suggest that apoptosis-linked gene networks similarly dysregulated in both IPF and a mouse model of TGFα-induced pulmonary fibrosis. TGFα mice treated with nintedanib show increased active caspase 3-positive cells in fibrotic lesions and reduced fibroproliferation and collagen production. Further, the long-term nintedanib therapy attenuated fibrocyte accumulation, collagen deposition, and lung function decline during TGFα-induced pulmonary fibrosis. These results highlight the importance of inhibiting survival pathways and other pro-fibrotic processes in the various types of mesenchymal cells and suggest that the TGFα mouse model is relevant for testing of anti-fibrotic drugs either alone or in combination with nintedanib.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with aberrant activation of fibroblasts, leading to their excessive proliferation, survival, accumulation, and production of the extracellular matrix (ECM) (Hardie et al, 2009)
Nintedanib Induces Apoptotic Clearance of Lung-Resident Myofibroblasts In idiopathic pulmonary fibrosis (IPF), the ECM-producing myofibroblasts that accumulate in fibrotic lung lesions develop resistance to apoptosis (Frankel et al, 2006; Thannickal and Horowitz, 2006)
We observed a significant increase in cleaved caspase-3 activity and, more apoptotic cells in lung-resident myofibroblasts treated with nintedanib compared to vehicle alone (Figures 1A,B)
Summary
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with aberrant activation of fibroblasts, leading to their excessive proliferation, survival, accumulation, and production of the extracellular matrix (ECM) (Hardie et al, 2009). Two US Food and Drug Administration (FDA)-approved drugs, Ofev (nintedanib) and Esbriet (pirfenidone), are available as new therapies for IPF patients. They improve lung function, the mechanisms underlying their effects remain largely unknown (King et al, 2014; Richeldi et al, 2014; Nathan et al, 2017). With persistent injury and excessive growthfactor production, resistance to apoptotic clearance develops in myofibroblasts and fibrotic lung lesions continuously expand (Wynn, 2007; Marudamuthu et al, 2015). Understanding the molecular controls of this dysfuction will clear the way for developing effective antifibrotic drugs
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