Role of Platelet-Derived Transforming Growth Factor-β1 and Reactive Oxygen Species in Radiation-Induced Organ Fibrosis. Review uri icon

Overview

abstract

  • SIGNIFICANCE: This review evaluates the role of platelet-derived transforming growth factor (TGF)-β1 in oxidative stress-linked pathologic fibrosis, with an emphasis on the heart and kidney, by using ionizing radiation as a clinically relevant stimulus. Current radiation-induced organ fibrosis interventions focus on pan-neutralization of TGF-β or the use of anti-oxidants and anti-proliferative agents, with limited clinical efficacy. Recent Advances: Pathologic fibrosis represents excessive accumulation of collagen and other extracellular matrix (ECM) components after dysregulation of a balance between ECM synthesis and degradation. Targets based on endogenous carbon monoxide (CO) pathways and the use of redox modulators such as N-acetylcysteine present promising alternatives to current therapeutic regimens. CRITICAL ISSUES: Ionizing radiation leads to direct DNA damage and generation of reactive oxygen species (ROS), with TGF-β1 activation via ROS, thrombin generation, platelet activation, and pro-inflammatory signaling promoting myofibroblast accumulation and ECM production. Feed-forward loops, as TGF-β1 promotes ROS, amplify these profibrotic signals, and persistent low-grade inflammation insures their perpetuation. We highlight differential roles for platelet- versus monocyte-derived TGF-β1, establishing links between canonical and noncanonical TGF-β1 signaling pathways in relationship to macrophage polarization and autophagy, and define points where pharmacologic agents can intervene. FUTURE DIRECTIONS: Additional studies are needed to understand mechanisms underlying the anti-fibrotic effects of current and proposed therapeutics, based on limiting platelet TGF-β1 activity, promotion of macrophage polarization, and facilitation of collagen autophagy. Models incorporating endogenous CO and selective TGF-β1 pathways that impact the initiation and progression of pathologic fibrosis, including nuclear factor erythroid 2-related factor (Nrf2) and redox, are of particular interest. Antioxid. Redox Signal. 27, 977-988.

publication date

  • July 5, 2017

Research

keywords

  • Heart Diseases
  • Liver Cirrhosis
  • Radiotherapy
  • Reactive Oxygen Species
  • Transforming Growth Factor beta1

Identity

PubMed Central ID

  • PMC5649128

Scopus Document Identifier

  • 85030246086

Digital Object Identifier (DOI)

  • 10.1089/ars.2017.7064

PubMed ID

  • 28562065

Additional Document Info

volume

  • 27

issue

  • 13