ESTRO 2024 - Abstract Book

S5263

Radiobiology - Normal tissue radiobiology

ESTRO 2024

Keywords: radiation-induced lung fibrosis, NLRP3, NXC736

1598

Digital Poster

A synthetic LipoxinA4 analog improves radiation-induced lung injury by modulating NFκB signaling

Sunjoo Park, Ronglan Cui, Hai In Jo, Sang Yeon Kim, Hyo Jeong Song, Jae Hee Lee, Moharmed El Agamy Farh, Jaeho Cho

Yonsei University College of Medicine, Department of Radiation Oncology, Seoul, Korea, Republic of

Purpose/Objective:

Radiation used for therapeutic proposes can cause side-effects in the surrounding normal tissues adjacent to the tumor. If this damage progresses chronically, it may result in various lung conditions, such as radiation pneumonia or pulmonary fibrosis. Lipoxin A4 (LXA4), a metabolic product of arachidonic acid, has potent dual pro-resolving and anti-inflammatory properties. However, the metabolic instability of endogenously produced LXA4 has somewhat limited its therapeutic utility. Therefore, in an effort to reduce radiation-induced damage to nearby normal tissues, we designed a synthetic analogue of LXA4 (sLX) to prevent rapid metabolic inactivation and degradation. Subsequently, we investigated the effects of native LXA4(nLX) and its analogue in radiation-induced lung injury (RILI) through in vitro cell culture and in vivo animal experiments.

Material/Methods:

The biologic activity of the synthetic LXA4 analogue has been assessed in the context of inflammatory responses, including NF-kB activity and cytokine release in LPS-induced THP1 monocyte cell line stably expressing an NF-κB luciferase reporter. The relative potency of synthetic LXA4 analogue versus native LXA4 was evaluated across varied parameters of inflammation and fibrosis in human epithelial cell. Finally, we established a mouse model with focal radiation-induced lung injury and utilized FPR2(formyl peptide receptor 2; lipoxin A4 receptor) deficient mice models to validation the efficacy of the synthetic LXA4 analogue.

Results:

The synthetic LXA4 analogue displayed a higher biological activity compared to native LXA4 in LSP-stimulated THP1 cells and radiation-induced L132 epithelial cells. Both LXA4 and its analogue facilitates the cell viability and not affected cell cytotoxicity. In radiation-induced epithelial cell, LXA4 and its analogue inhibited NF-κB activation, decreased the secretion of pro-inflammatory cytokines, prevented the apoptosis of lung cells, and inhibited p AMPK/Samd3 activation, thereby exerting protective effects against RILI. In a radiation-induced lung inflammation mouse model, the injection of LXA4 analogue lead to downregulation of pro-inflammatory cytokines such as TNF α, IL-1β, IL-6, and TGF-β in the tissue. It also suppressed the phosphorylation of nuclear factor kappa-B (NF-κB) p65, c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinase (Erk), and p38. In a radiation-induced lung fibrosis mouse model, the treatment of LXA4 analogue showed significant improvements in collagen deposition, SMA deletion, and fibronectin reduction, and functional lung parameters. These therapeutic effects were better than those of native LXA4. As a result, the synthetic LXA4 analogue demonstrates exhibits anti-inflammatory and