DR7dA, a Novel Antioxidant Peptide Analog, Demonstrates Antifibrotic Activity in Pulmonary Fibrosis In Vivo and In Vitro

Abstract

Pulmonary fibrosis (PF), which is characterized by enhanced extracellular matrix (ECM) deposition, is an interstitial lung disease that lacks an ideal clinical treatment strategy. It has an extremely poor prognosis, with an average survival of 3-5 years after diagnosis. Our previous studies have shown that the antioxidant peptide DR8 (DHNNPQIR-NH 2 ), which is extracted and purified from rapeseed, can alleviate PF and renal fibrosis. However, natural peptides are easily degraded by proteases in vivo, which limits their potency. We have since synthesized a series of DR8 analogs based on amino acid scanning substitution. DR7dA (DHNNPQ (D-alanine) R-NH 2 ) is an analog of DR8 in which L-isoleucine (L-Ile) is replaced with D-alanine (D-Ala), and its half-life is better than that of DR8. In the current study, we verified that DR7dA ameliorated TGF-β1-induced fibrogenesis and bleomycin-induced PF. The results indicated that DR7dA reduced the protein and mRNA levels of TGF-β1-target genes in TGF-β1-induced models. Surprisingly, DR7dA blocked fibrosis in a lower concentration range than DR8 in cells. In addition, DR7dA ameliorated tissue pathological changes and ECM accumulation in mice. BLM caused severe oxidative damage, but administration of DR7dA reduced oxidative stress and restored antioxidant defense. Mechanistic studies suggested that DR7dA inhibits ERK, P38 and JNK phosphorylation in vivo and in vitro. All results indicated that DR7dA attenuated PF by inhibiting ECM deposition and oxidative stress via blockade of the MAPK pathway. Hence, compared with its parent peptide, DR7dA has higher druggability and could be a candidate compound for PF treatment in the future.

Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis

“…Pulmonary fibrosis (PF) is the end-stage consequence of various interstitial lung diseases (ILD). It is a chronic progressive disease with an average survival of 3-5 years after diagnosis [1]. PF results from the dysregulation of alveolar epithelial cell (AECs) repair in response to alveolar and vascular damage, which leads to the excessive accumulation of ECM, proliferation of myofibroblasts, distortion of pulmonary architecture, and loss of pulmonary tissue function [2].…”