Feedback between damaged epithelial and senescent fibroblast promotes pulmonary fibrosis

Idiopathic pulmonary fibrosis is a progressive, aging-related lung disease in which fibroblast senescence drives scarring, yet what sustains that senescence is unclear. Here we show that injured alveolar epithelial cells and senescent fibroblasts reinforce each other through a self-amplifying circuit. In fibrotic human and mouse lungs, sphingosine kinase 1 is induced selectively in injured epithelium, whereas senescence markers accumulate in fibroblasts. Epithelium-derived sphingosine-1-phosphate engages the receptor S1PR3 on fibroblasts, activates phosphoinositide 3-kinase-AKT-mTOR signaling, suppresses autophagy and drives senescence. Senescent fibroblasts in turn secrete interleukin-6, which activates STAT3 in epithelial cells and reactivates sphingosine kinase 1 transcription, closing the loop. Deleting sphingosine kinase 1 globally, or silencing it selectively in alveolar epithelium, reduces bleomycin-induced fibrosis in mice, as does pharmacological blockade of either the kinase or its receptor. These findings define an epithelial-fibroblast feedback circuit that sustains lung fibrosis and nominate it as a therapeutic target.