Role of hypusine signaling in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease. Co-morbid pulmonary hypertension (PH) is common in patients with IPF and contributes to a worse clinical prognosis. Exaggerated resistance to apoptosis, enhanced proliferation and excessive extracellular matrix (ECM) deposition are key endophenotypes observed in both lung fibroblasts (LFs) and pulmonary artery smooth muscle cells (PASMCs) from IPF patients resulting in the development and perpetuation of fibrotic scarring and vascular obliteration. Eukaryotic translation initiation factor 5A (eIF5A) is known to facilitate translation of mRNAs with oncogenic proprieties and containing consecutive proline residues. Strikingly, eIF5A is the only protein that contains the post-translational modification hypusine, which is required for its function. Hypusine formation is catalyzed by the sequential actions of Deoxyhypusine synthase (DHPS) and Deoxyhypusine hydroxylase (DOHH). We hypothesized that hypusine signaling is increased in IPF and promotes parenchymal and vascular remodeling. We demonstrated that DHPS, DOHH, total and hypusinated forms of eIF5A are overexpressed in lungs and isolated LFs of IPF patients and animal models (bleomycin (BLM)-treated mice, BLM+MCT-treated rats). We found that pharmacological inhibition of DHPS (GC7) reduced IPF-LF and IPF-PASMC survival and proliferation (Annexin V, Ki67, EdU incorporation), activation (aSMA, FN, COL1) and migratory capacity (scratch-wound and transwell assays). GC7 or genetic deletion of DHPS reduced TGFb1-induced activation of control LFs (Survivin, aSMA and COL1). Inhibition of DHPS improved fibrosis in human IPF-PCLS. Our data show that hypusine signaling may represent a new therapeutic target in IPF.