# Pexidartinib and Nintedanib Combination Therapy Targets Macrophage Polarization to Reverse Pulmonary Fibrosis: A Preclinical Study

## TL;DR

This preclinical study explores how combining two drugs can reverse lung scarring by targeting immune cell changes in a mouse model of a deadly lung disease.

## Contribution

The study introduces a novel combination therapy targeting macrophage polarization to reverse pulmonary fibrosis.

## Key findings

- Combination therapy with nintedanib and pexidartinib inhibited radiation-induced pulmonary fibrosis and improved survival in mice.
- The treatment normalized abnormal vascular structures and reduced M2 macrophage populations in fibrotic lungs.
- Single-cell RNA sequencing in IPF patients showed upregulated CSF1 and downregulated capillary markers in macrophages.

## Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options and increasing global incidence, with a median survival of only 2–5 years. The clinical utility of macrophage polarization to regulate the progression of pulmonary fibrosis remains understudied. This study determined the efficacy of nintedanib and pexidartinib (PLX3397) combination therapy for treating IPF. Combination treatment effectively inhibited the progression of radiation-induced pulmonary fibrosis (RIPF) and prolonged survival in bleomycin-treated mice. Micro-CT analysis revealed a significant tissue repair efficacy. The therapy significantly normalized the abnormal vascular structure observed during RIPF and bleomycin-induced pulmonary fibrosis progression and was accompanied by a decrease in the M2 population. Polarized M1 macrophages enhanced normalized tube formation of irradiated endothelial cells (ECs) in vitro; M2 macrophages increased adhesion in irradiated ECs and abnormal tube formation. Single-cell RNA sequencing data from patients with IPF further supports colony stimulating factor (CSF) 1 upregulation in macrophages and downregulation of capillary EC markers. This study highlights a promising combination strategy to overcome the therapeutic limitations of monotherapy with nintedanib for the treatment of IPF.