RNA Sequencing Uncovers Antifibrotic Genes During Lung Fibrosis Resolution

Progressive scarring of the lungs is a lethal outcome of idiopathic pulmonary fibrosis (IPF) (1). The U.S. Food and Drug Administration–approved drugs nintedanib and pirfenidone have been shown to reduce the rate of progression of IPF; however, they cannot halt or reverse lung fibrosis (2). The mechanisms of action of these drugs remain poorly understood, but they likely target pathways involved in lung fibrosis initiation and development (3) rather than mechanisms promoting fibrosis resolution. Thus, further understanding of the biological and molecular mechanisms promoting resolution of persistent lung fibrosis is desperately needed to develop novel drugs that may reverse lung fibrosis, ultimately inducing regeneration of the damaged lung tissue. In this issue of the Journal, Tan and colleagues (pp. 453–464) describe studies using RNA-sequencing (RNA-seq) analysis to identify endogenous antifibrotic genes that promote resolution of lung fibrosis in vivo in mouse models of lung fibrosis (4). Lung fibrosis has traditionally been considered an irreversible process. Although the lungs lack the dramatic regenerative capacity of the liver (5), lung fibrosis has been shown to spontaneously resolve in human lung diseases, including acute respiratory distress syndrome, severe acute respiratory syndrome, and coronavirus disease (COVID-19) (6–9). Similarly, lung fibrosis resolves in most murine lung injury models induced by LPS, bleomycin, asbestos fibers, or FITC (5, 10, 11), especially in commonly used young C57BL/6 mice. Taking advantage of these self-resolving models of lung fibrosis in young mice, Tan and colleagues applied RNA transcriptomics to identify genes and mechanisms associated with fibrosis resolution in the bleomycin-induced lung fibrosis model. They first investigated changes in gene expression of primary lung fibroblasts isolated from healthy lungs compared with fibroblasts isolated from lungs of bleomycin-challenged mice at Day 14 (peak of fibrosis) and Day 30 (early-stage fibrosis resolution). Notably, the authors used the Col1a1-GFP reporter mouse to facilitate fluorescence-activated cell sorting of collagen-producing cells in this model before RNA-seq analysis (12). They identified 3,018 candidate genes whose expression was increased/decreased during the peak of lung fibrosis