Cellular senescence has been increasingly implicated in the development of pulmonary fibrosis, a largely irreversible condition with a poor prognosis under the current standard of care. An early clinical trial of first generation senolytic drugs to clear senescent cells showed promising results, but the condition remains a low priority among companies developing various forms of novel senolytics. Here, researchers discuss one of the primary mechanisms targeted by early senolytics, the BCL-2 protein known to be involved in preventing apoptosis in senescent cells, in the context of pulmonary fibrosis.
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.
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