Insulin-like growth factor 1 by lung fibroblasts from patients with idiopathic pulmonary fibrosis contributes to the development of fibrosis.

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of interstitial pneumonia with a poor prognosis. IPF is mainly caused by the excessive synthesis and accumulation of the extracellular matrix produced by myofibroblasts. However, the mechanisms underlying the disease progression of IPF have not been fully elucidated.

METHODS

To identify fibrosis-associated genes while minimizing genetic heterogeneity, pulmonary fibroblasts were derived from paired non-fibrotic (NF) and fibrotic (F) areas of lungs from patients with IPF, and gene expression profiles were compared. Functional analyses of fibroblasts were performed by stimulation with transforming growth factor-β (TGF-β) and/or insulin-like growth factor 1 (IGF-1), or by the pharmacological inhibition of TGF-β and IGF-1 receptor (IGF-1R) signaling.

RESULTS

IGF-1 expression was significantly higher in lung F areas than in the NF areas of IPF lungs. IGF-1 expression was positively correlated with fibrotic marker genes. Stimulation of IPF lung fibroblasts with TGF-β induced time-dependent increases in IGF-1 and α-smooth muscle actin expression, whereas the inhibition of TGF-β signaling suppressed IGF-1 expression. Although IGF-1 itself did not enhance fibrotic marker expression, co-stimulation with TGF-β augmented TGF-β-driven profibrotic gene expression. Furthermore, the inhibition of IGF-1R signaling with OSI-906, a selective IGF-1R inhibitor, attenuated fibrotic marker expression under TGF-β alone and TGF-β plus IGF-1 stimulation conditions.

CONCLUSIONS

These results suggest that IGF-1 amplifies TGF-β-driven profibrotic responses and may represent a potential therapeutic target for IPF.