Conditional Fibroblast BCL-2 Expression Promotes Persistent Pulmonary Fibrosis, which is Reversible by Therapeutic BCL-2 Inhibition

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that develops in response to chronic epithelial injury. Unlike homeostatic lung repair and regeneration following injury, the lungs of IPF patients accumulate apoptosis-resistant, pro-fibrotic, extracellular matrix producing fibroblasts. It has been 10 years since the introduction of two FDA-approved, though relatively ineffective, therapies. Thus, there is a dire need for mechanistic investigations to enable new therapeutics to enter clinical trails. Here, using the normally resolving model of bleomycin-induced lung injury and newly engineered mice that express human BCL-2 in PDGFRa+ alveolar fibroblasts along with studies in IPF lung tissues, we show that BCL-2 blocks fibroblast apoptosis, which is crucial for lung regeneration. This inhibition leads to the emergence of senescent, pro-fibrotic fibroblasts along with persistent, pathologic, fibrotic lung remodeling. Conversely, selective BCL-2 inhibition with ABT-199 (VenetoclaxTM) in fibrotic mice re-engaged the apoptotic pathway, reduced senescence, caused fibroblast elimination, and promoted fibrosis resolution and lung regeneration. Our findings suggest that sustained BCL-2 expression in fibroblasts prevents homeostatic lung repair, drives persistent fibrosis and is a therapeutically relevant target to reverse persistent pulmonary fibrosis. Overall design: Naive, 3wk bleomycin hBcl2, 3wk bleomycin Wild Type/CO, 6wk bleomycin hBcl2, 6wk bleomtcin Wild Type/CO