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

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-

• Khan, M. M.
• Galea, G.
• Jung, J.
• Zukowska, J.
• Lauer, D.
• Tuechler, N.
• Halavatyi, A.
• Tischer, C.
• Haberkant, P.
• Stein, F.
• Jung, F.
• Landry, J. J. M.
• Khan, A. M.
• Oorschot, V.
• Becher, I.
• Neumann, B.
• Muley, T.
• Winter, H.
• Duerr, J.
• Mall, M. A.
• Grassi, A.
• de la Cueva, E.
• Benes, V.
• Gote-Schniering, J.
• Savitski, M.
• Pepperkok, R.