Anti-Fibrotic Peptide B7-33 and FOXO4-DRI as Potential Therapies for COPD, Emphysema, and Lung Fibrosis

by Dr. James Ross

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Senescent “Zombie” Cells Drive Lung Inflammation

In chronic lung conditions such as COPD and emphysema, senescent cells—often referred to as “zombie cells”—accumulate in tissues. These cells no longer divide but remain metabolically active, releasing inflammatory molecules, proteases, and other damaging factors. Collectively known as the senescence-associated secretory phenotype (SASP), these secretions worsen oxidative stress, DNA damage, and inflammation in neighboring cells. This creates a self-propagating cycle of tissue injury and declining lung function.

FOXO4-DRI Selectively Clears Damaging Senescent Cells

One therapeutic strategy involves eliminating senescent cells directly. FOXO4-DRI is a peptide that induces apoptosis specifically in senescent cells without harming healthy ones. Research has shown that FOXO4-DRI clears cells that have entered senescence due to DNA damage (such as after chemotherapy exposure) but does not increase sensitivity to DNA damage in normal cells. This selective action makes it a promising senolytic candidate for chronic diseases linked to cellular aging.

SASP Secretion and Senescent Cell Removal

Interestingly, although chronic SASP release drives disease progression, transient increases in SASP signaling can make senescent cells more vulnerable to removal. In laboratory studies, FOXO4-DRI was most effective at eliminating senescent cells producing high levels of SASP factors like IL-6. This indicates that in conditions with elevated inflammatory signals—such as chronic lung disease—senolytics may be even more effective.

The concept aligns with broader findings in other diseases, such as type 1 diabetes, where timely clearance of SASP-expressing cells prevents excessive fibrosis and tissue destruction.

B7-33: A Next-Generation Anti-Fibrotic Peptide

Alongside senolytic therapies, anti-fibrotic peptides like B7-33 are being explored for their potential to protect lung tissue. B7-33 is a derivative of relaxin-2, a peptide hormone known for its vasodilatory and anti-fibrotic properties. Unlike traditional RXFP1 activators, which rely heavily on cAMP signaling, B7-33 triggers ERK1/2 pathways without significantly increasing cAMP. This “biased signaling” is beneficial, as excessive cAMP activity has been linked to harmful effects in conditions such as heart failure.

Reversal of Fibrosis in Lung Disease Models

In animal studies of allergic airway disease, B7-33 completely reversed airway thickening, reduced collagen build-up, and improved lung function. Treated mice showed normalized collagen levels and a significant improvement in airway responsiveness, comparable to the parent peptide relaxin-2. Importantly, B7-33 improved both airway remodeling and functional performance, key outcomes for diseases such as COPD and emphysema.

Protective Effects Across Multiple Organs

B7-33’s benefits extend beyond the lungs. In models of heart injury, B7-33 reduced cardiac fibrosis by about 50%, nearly matching the effects of relaxin-2. Similar anti-fibrotic activity has been observed in the kidneys and liver, highlighting its broad potential as a systemic therapy against fibrotic diseases. Unlike relaxin-2, B7-33 avoids certain drawbacks such as promoting tumor growth, making it a safer candidate for long-term use.

REFERENCES

1. Rashid, K., Sundar, I.K., Gerloff, J. et al. Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema. Sci Rep 8, 9023 (2018). https://doi.org/10.1038/s41598-018-27209-3
2. Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031. PMID: 28340339; PMCID: PMC5556182.