Selective BCL-2 inhibition with ABT-199 in fibrotic mice significantly reduced PDGFRα+ lung fibroblasts (p<0.001), reversed senescence, and promoted fibrosis resolution and lung regeneration.
Does BCL-2 inhibition with ABT-199 promote fibrosis resolution and lung regeneration in preclinical models of persistent pulmonary fibrosis?
Pharmacological targeting of BCL-2 with ABT-199 reverses fibroblast senescence and promotes fibrosis resolution in preclinical models of persistent pulmonary fibrosis.
p-value: p=<0.001
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that develops in response to chronic epithelial injury. Unlike injury-induced homeostatic lung repair during which fibroblasts undergo apoptosis and clearance, the lungs of IPF patients continue to accumulate apoptosis-resistant, pro-fibrotic, extracellular matrix-producing fibroblasts. Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression leads to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring, pathologic fibrotic lung remodeling. Additionally, spatial transcriptomic studies of human IPF lungs confirmed the presence of senescent, BCL-2 expressing α-smooth muscle actin+ myofibroblasts in fibrotic regions. Of translational significance, selective BCL-2 inhibition with ABT-199 in fibrotic mice re-engaged the apoptotic pathway in fibroblasts, reduced senescence, 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.
Redente et al. (Sat,) conducted a other in Idiopathic pulmonary fibrosis. ABT-199 (Venetoclax) vs. Vehicle was evaluated on Reduction in PDGFRα+ lung fibroblasts (p=<0.001). Selective BCL-2 inhibition with ABT-199 in fibrotic mice significantly reduced PDGFRα+ lung fibroblasts (p<0.001), reversed senescence, and promoted fibrosis resolution and lung regeneration.