Kim, Hyelim Park, Chai Won Kim, Jisun Kim, Seong-Eun Ahn, June Hong Seong, Je Kyung Lee, Wonhwa Cho, Seung-Woo Kim, Hong Nam 2026-01-15T08:00:17Z 2026-01-15T08:00:17Z 2026-01-12 2025-12 https://pubs.kist.re.kr/handle/201004/154007 Post-infectious pulmonary fibrosis remains difficult to prevent due to limited mechanistic understanding and the lack of human-relevant models. We engineered an immune-integrated lung-on-a-chip incorporating endothelial cells, fibroblasts, and macrophages to dissect early fibrotic signaling. Intravascular exposure to thymocyte selection-associated high mobility group box protein (TOX), a T cell–derived factor elevated after severe infection, impaired endothelial barrier function, upregulated intercellular adhesion molecule-1 (ICAM-1), and, through macrophages, induced fibroblast activation with increased α-smooth muscle actin (α-SMA), fibronectin, and extracellular matrix (ECM) remodeling. Pre-treatment with a receptor for advanced glycation end products (RAGE)-blocking antibody preserved barrier integrity and suppressed macrophage activation, fibroblast expansion, and collagen bundling. Similar protective effects were observed in a mouse model of TOX-induced fibrosis, where RAGE blockade improved survival and reduced collagen deposition. Analysis of profibrotic mediators revealed a conserved TOX–RAGE–macrophage signature across the chip model, mouse lungs, and patient bronchoalveolar lavage fluid (BALF) samples. These results identify TOX–RAGE signaling as a driver of post-infectious fibrotic remodeling and establish RAGE blockade as a potential preventive strategy. English Springer | Korea Nano Technology Research Society Engineering an immune-integrated lung-on-a-chip to reveal TOX–RAGE axis–driven fibrosis and RAGE blockade as a therapeutic strategy Article 10.1186/s40580-025-00529-7 1 Nano Convergence, v.12, no.1 Nano Convergence 12 1 Y scie scopus kci 001642642600001 2-s2.0-105025132862 Nanoscience & Nanotechnology Materials Science, Multidisciplinary Physics, Applied Science & Technology - Other Topics Materials Science Physics Article Lung-on-a-chip Fibrosis Macrophage TOX RAGE