In a promising breakthrough, researchers have achieved the reversal of lung fibrosis in a mouse model of idiopathic pulmonary fibrosis (IPF). Published in the journal Cell Death and Differentiation, the study details how mice, afflicted with lung fibrosis induced by bleomycin, were treated with ABT-199, also known as Venetoclax – an FDA-approved medication for leukemia.
The results were nothing short of remarkable: while untreated mice exhibited extensive lung scarring, those receiving ABT-199 treatment showcased normal lung architecture with no signs of collagen deposition.
Led by Dr. A. Brent Carter, Professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Alabama at Birmingham (UAB), alongside first author Dr. Linlin Gu, the study provides a groundbreaking insight into tackling pulmonary fibrosis, a chronic condition characterized by abnormal lung tissue remodeling.
Idiopathic pulmonary fibrosis, the most prevalent form, presents a dire prognosis with high mortality rates within three to five years, despite currently available treatments showing limited effectiveness.
The key to the breakthrough lies in ABT-199’s ability to induce apoptosis, or programmed cell death, in lung macrophages – large white blood cells crucial for immune response. Notably, previous understanding suggested that fibrosis progression was linked to apoptosis resistance in these macrophages, with mitochondria playing a pivotal role in this mechanism.
Through meticulous analysis of lung macrophages isolated from IPF patients and bleomycin-exposed mice, the researchers identified elevated levels of mitochondrial proteins Bcl-2, MCU, and Cpt1a. Of particular significance was the interaction between Cpt1a and Bcl-2, which effectively stabilized Bcl-2 within the mitochondria, thwarting apoptosis. This revelation paved the way for targeted interventions aimed at disrupting this interaction, ultimately reversing fibrosis progression in mouse models.
Furthermore, genetic experiments involving the conditional deletion of Bcl-2 in lung macrophages provided compelling evidence of its role in fibrosis. Mice lacking Bcl-2 were shielded from both bleomycin and asbestos-induced lung fibrosis, underscoring its potential as a therapeutic target.
Dr. Carter emphasizes the significance of these findings, not only in unraveling the intricate mechanisms underlying fibrosis but also in identifying a novel therapeutic avenue to combat this relentless disease. With further research and clinical validation, these insights hold the promise of transforming the landscape of pulmonary fibrosis treatment, offering renewed hope to countless patients battling this debilitating condition.
The study was supported by grants from the National Institutes of Health, Department of Veterans Affairs, and Pulmonary Fibrosis Foundation, underscoring the collaborative effort driving breakthroughs in pulmonary research.
- Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling. Cell Death & Differentiation, 2021; DOI: 10.1038/s41418-021-00840-w
