Dextromethorphan inhibits collagen and collagen-like cargo secretion to ameliorate lung fibrosis

• Published in: Science translational medicine 2024-12, Vol.16 (778), p.eadj3087
• Main Authors: Khan, Muzamil M, Galea, George, Jung, Juan, Zukowska, Joanna, Lauer, David, Tuechler, Nadine, Halavatyi, Aliaksandr, Tischer, Christian, Haberkant, Per, Stein, Frank, Jung, Ferris, Landry, Jonathan J M, Khan, Arif M, Oorschot, Viola, Becher, Isabelle, Neumann, Beate, Muley, Thomas, Winter, Hauke, Duerr, Julia, Mall, Marcus A, Grassi, Alessandro, de la Cueva, Ernesto, Benes, Vladimir, Gote-Schniering, Janine, Savitski, Mikhail, Pepperkok, Rainer
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Bleomycin; Collagen; Collagen (type I); Collagen - metabolism; Collagen Type I - metabolism; Cough; Dextromethorphan; Dextromethorphan - pharmacology; Dextromethorphan - therapeutic use; Disease Models, Animal; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; Humans; Hydroxylation - drug effects; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung diseases; Membrane trafficking; Mice; Mice, Inbred C57BL; Molecular modelling; Proteomes; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Secretion; Thermal stability; Transcriptomes; Wnt protein
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.adj3087

Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, no cure for pulmonary fibrosis has yet been found. We screened a drug library and found that dextromethorphan (DXM), a cough expectorant, reduced the amount of excess fibrillar collagen deposited in the ECM in cultured primary human lung fibroblasts, a bleomycin mouse model, and a cultured human precision-cut lung slice model of lung fibrosis. The reduced extracellular fibrillar collagen upon DXM treatment was due to reversible trafficking inhibition of collagen type I (COL1) in the endoplasmic reticulum (ER) in TANGO1- and HSP47-positive structures. Mass spectrometric analysis showed that DXM promoted hyperhydroxylation of proline and lysine residues on various collagens (COL1, COL3, COL4, COL5, COL7, and COL12) and latent transforming growth factor-β-binding protein (LTBP1 and LTBP2) peptides, coinciding with their secretion block. Additionally, proteome profiling of DXM-treated cells showed increased thermal stability of prolyl-hydroxylases P3H2, P3H3, P3H4, P4HA1, and P4HA2, suggesting a change in their activity. Transcriptome analysis of profibrotic stimulated primary human lung fibroblasts and human ex vivo lung slices after DXM treatment showed activation of an antifibrotic program through regulation of multiple pathways, including the MMP-ADAMTS axis, WNT signaling, and fibroblast-to-myofibroblast differentiation. Together, these data obtained from in vitro, in vivo, and ex vivo models of lung fibrogenesis show that DXM has the potential to limit fibrosis through inhibition of COL1 membrane trafficking in the ER.