Dysregulation of Mesenchymal Cell Survival Pathways in Severe Fibrotic Lung Disease: The Effect of Nintedanib Therapy

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

Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis

Fibroblast activation including proliferation, survival, and ECM production is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multiple pro‐fibrotic growth factors, including TGFα, CTGF, and IGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediates TGFα‐driven AURKB upregulation in fibroblasts. Importantly, we found that inhibition of AURKB expression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced by TGFα is highly dependent on AURKB expression and treating TGFα mice with barasertib, an AURKB inhibitor, reverses fibroblast activation, and pulmonary fibrosis. Barasertib similarly attenuated fibrosis in the bleomycin model of pulmonary fibrosis. Together, our preclinical studies provide important proof‐of‐concept that demonstrate barasertib as a possible intervention therapy for IPF.SynopsisFibroblast activation is central for the initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis. Our preclinical study describes the pathological role for AURKB in fibroblast activation and presents a potential therapy for the treatment of pulmonary fibrosis using barasertib.AURKB is upregulated in the lungs of IPF patients and mouse models of pulmonary fibrosis.WT1 binds directly to the promoter of AURKB to upregulates its expression.AURKB functions as a positive regulator of fibroproliferation, myofibroblast survival, and ECM production.In vivo barasertib therapy attenuates TGFα‐and bleomycin‐induced pulmonary fibrosis.Fibroblast activation is central for the initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis. Our preclinical study describes the pathological role for AURKB in fibroblast activation and presents a potential therapy for the treatment of pulmonary fibrosis using barasertib.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/7/emmm202012131-sup-0003-SDataFig1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/6/emmm202012131-sup-0002-EVFigs.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/5/emmm202012131-sup-0006-SDataFig6.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/4/emmm202012131.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/3/emmm202012131-sup-0005-SDataFig4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/2/emmm202012131-sup-0001-Appendix.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/1/emmm202012131_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/9/emmm202012131.reviewer_comments.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162746/8/emmm202012131-sup-0004-SDataFig2.pd

Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis

Abstract Fibroblast activation including proliferation, survival, and ECM production is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multiple pro‐fibrotic growth factors, including TGFα, CTGF, and IGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediates TGFα‐driven AURKB upregulation in fibroblasts. Importantly, we found that inhibition of AURKB expression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced by TGFα is highly dependent on AURKB expression and treating TGFα mice with barasertib, an AURKB inhibitor, reverses fibroblast activation, and pulmonary fibrosis. Barasertib similarly attenuated fibrosis in the bleomycin model of pulmonary fibrosis. Together, our preclinical studies provide important proof‐of‐concept that demonstrate barasertib as a possible intervention therapy for IPF