PBI-4050 reduces expression of fibrosis biomarkers in the BioMAP SAEMyoF primary human small airway epithelial cells and lung myofibroblasts system

Abstract

PBI-4050 is a novel orally active compound which displays anti-inflammatory/anti-fibrotic activities and is presently in clinical phase II in idiopathic pulmonary fibrosis (IPF), in metabolic syndrome associated with diabetes, and in cystic fibrosis related diabetes. The aim of this study was to determine the effect of PBI-4050 in the BioMAP SAEMyoF primary human cell fibrotic lung disease model. The BioMAP SAEMyoF system is a co-culture of TGF-β/TNF-α-stimulated primary human small airway epithelial cells and lung myofibroblasts that models the biology of fibrotic lung diseases such as IPF. Protein biomarker expression levels relative to vehicle control were determined in cells treated with PBI-4050, and compared to treatments with the anti-fibrotic drug pirfenidone and the tyrosine kinase inhibitor nintedanib. PBI-4050 key activities included a significant decrease of myofibroblast activation (α-SMA and N-cadherin) and of extracellular matrix production (collagen I and III). PBI-4050 also showed tissue remodeling (reduced MMP9 and PAI-1, increased MMP1) and inflammation-related (reduced I-TAC, M-CSF, MCP-1, IP-10) activities. Pirfenidone had a generally similar profile to PBI-4050, with the exception of increases in VCAM-1, MMP9 and TIMP-1 expression that were not obtained with PBI-4050 treatment. Unlike PBI-4050, nintedanib treatment did not result in reduced α-SMA, N-cadherin, and M-CSF expression, nor increased MMP1. Our results demonstrate that PBI-4050 reduces myofibroblast activation, extracellular matrix production and inflammation in a primary human cell system modeling fibrotic lung diseases, and is a potential novel therapy for the treatment of IPF.