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Antioxid Redox Signal. 2017 Nov 1;27(13):977-988. doi: 10.1089/ars.2017.7064. Epub 2017 Jul 5.

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

Author information

1
1 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma.
2
2 Division of Hematology and Medical Oncology, Weill Cornell Medical College , New York, New York.

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.

KEYWORDS:

cardiovascular disease; chronic kidney disease; collagen autophagy; fibrosis; ionizing radiation; macrophage polarization; transforming growth factor

PMID:
28562065
PMCID:
PMC5649128
DOI:
10.1089/ars.2017.7064
[Indexed for MEDLINE]
Free PMC Article

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