Exogenous tryptophan aggravates experimental lung fibrosis through activation of AKT-mTORC1 pathway

Idiopathic pulmonary fibrosis (IPF) is marked by aberrant lung remodeling and excessive extracellular matrix (ECM) accumulation. Previously, we observed elevated tryptophan (TRP) levels in the lungs of IPF patients, but its role in fibrogenesis remained unclear. This study examines whether TRP modulate the severity of lung fibrosis by measuring ECM component expression in TRP-treated lung fibroblasts. The activities of key TRP metabolism enzymes, tryptophan hydroxylase (TPH-1) and indoleamine 2,3-dioxygenase (IDO/TDO), were also assessed in IPF lung. Exogenous TRP administration in bleomycin-exposed mice significantly exacerbated lung damage and fibrosis. TPH-1 levels were elevated in lung tissues and primary fibroblasts of IPF patients compared to controls, while IDO/TDO expression showed no significant differences between two groups. TRP treatment increased fibroblast proliferation and upregulated collagen, fibronectin, and α-smooth muscle actin expression, whereas TRP deprivation reduced these ECM component levels. Additionally, TRP upregulated the AKT-mTORC1 and TGF-β1 signaling pathways in IPF fibroblasts. These findings indicate that elevated TRP levels contribute to IPF pathogenesis and suggest that targeting the TRP pathway could offer therapeutic potential for lung fibrosis including IPF.