Idiopathic Pulmonary Fibrosis Serum proteomic analysis before and after nintedanib therapy

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive disease with a median survival of 2-5 years. Nintedanib is a small tyrosine kinase inhibitor that reduces IPF progression, significantly slowing the annual decline in Forced Vital Capacity (FVC). Very little data is available on the molecular mechanisms of this treatment in IPF, despite a growing interest in the definition of IPF pathogenesis and target therapy. A functional proteomic approach was applied to the analysis of serum samples from IPF patients in order to highlight differential proteins potentially indicative of drug-induced molecular pathways modifications and response to therapy. Twelve serum samples were collected from six IPF patients in care at Siena Regional Referral Center for Interstitial Lung Diseases (ILDs) and treated with nintedanib for one year. Serum samples were analyzed at baseline (T0 before starting therapy) and after one year of treatment (T1) and underwent differential proteomic and bioinformatic analysis. Proteomic analysis revealed 13 protein species that were significantly increased after one year of treatment. When the targets of nintedanib (VEGFR, FGFR and PDGFR) were added, enrichment analysis extracted molecular pathways and process networks involved in cell differentiation (haptoglobin and albumin), coagulation (antithrombin III), epithelial mesenchymal transition, cell proliferation and transmigration. PI3K and MAPK induced up-regulation of apolipoprotein C3. Proteomic study found 13 protein species up-regulated in IPF patients after one year of nintedanib treatment. Haptoglobin, a central hub of our analysis was validated by 2D-WB and ELISA as theranostic marker in a more numerous populations of patients.

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

“…Indeed, in diabetic retinopathy, RAAS is an effector of vascular epithelial growth factor (VEGF) that drive the leakage of retinal blood vessels [ 50 ]. VEGF is also well known to be one of the major players in IPF onset and its receptor is one of the targets of nintedanib treatment [ 11 , 51 ].…”

“…PPAR-γ agonists promote adipocyte differentiation and adiponectin secretion [ 84 , 85 ]. Another recent proteomic study of ours on BAL protein modulation after the nintedanib treatment of IPF patients highlighted the up-regulated apolipoprotein C3 in serum after one year of nintedanib administration, linked to PPAR-γ by enrichment analysis [ 51 ].…”

Extracellular Vesicle Surface Signatures in IPF Patients: A Multiplex Bead-Based Flow Cytometry Approach

“…MCSP is a surface type I transmembrane core proteoglycan that is crucially involved in cell survival, migration, and angiogenesis [ 58 , 59 ]. However, since IPF pathobiology is characterized by epithelial dysfunction, altered epithelial-mesenchymal transition and consequent reparative processes, the increased expression of MCSP in EVs observed in our study may be related to aberrant neoangiogenesis processes associated with the pathogenetic mechanisms of IPF [ 60 ].…”

Genomics of Human Fibrotic Diseases: Disordered Wound Healing Response

“…Advances in therapies have led to the development and approval of two drugs that slow the rate of fibrosis and associated functional decline in IPF: nintedanib, a tyrosine kinase inhibitor that targets growth factor signaling downstream of VEGFR, FGFR, and PDGFR; pirfenidone, which exerts anti-inflammatory as well as anti-fibrotic effects via inhibition of collagen synthesis, downregulation of TGF-β and TNF alpha, and decreased fibroblast proliferation [ 177 ]. Proteomic analysis of serum from IPF patients at baseline and 1 year after nintedanib treatment identified differences in proteins related to cell differentiation and epithelial-mesenchymal transition [ 220 ]. Pamrevlumab, an antibody therapy targeting connective tissue growth factor, is currently in phase II clinical trials.…”