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Review
. 2019 Jan 1;34(1):43-55.
doi: 10.1152/physiol.00033.2018.

Mechanisms for the Resolution of Organ Fibrosis

Jeffrey C Horowitz  1 , Victor J Thannickal  2
Affiliations
Review

Mechanisms for the Resolution of Organ Fibrosis

Jeffrey C Horowitz et al. Physiology (Bethesda). .

Abstract

Fibrosis is a dynamic process with the potential for reversibility and restoration of near-normal tissue architecture and organ function. Herein, we review mechanisms for resolution of organ fibrosis, in particular that involving the lung, with an emphasis on the critical roles of myofibroblast apoptosis and clearance of deposited matrix.

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Figures

FIGURE 1.
FIGURE 1.
Homeostatic and fibrotic wound repair The host response to injury is a complex interplay of epithelial cells, mesenchymal cells, vascular endothelium, and inflammatory cells that are regulated by plasma proteins, coagulation factors, other soluble mediators synthesized from cells and/or liberated from protein-bound niches in the extracellular matrix, and mechanical cues transmitted to cells from the environment. Resolution of wound repair requires the highly orchestrated spatial and temporal regulation of these processes, which, when successful, culminate in the reestablishment of an intact epithelium coupled with degradation of extracellular matrix components and clearance of activated myofibroblasts. Intrinsic and extrinsic factors, including genetic/epigenetic background, the nature of the stimulus for injury, and the extent of the initial injury are additional factors that determine the outcome of wound repair.
FIGURE 2.
FIGURE 2.
Mechanisms of non-resolving fibrosis Resolution of fibrosis requires the orchestrated apoptosis of myofibroblasts, and the degradation and clearance of deposited matrix molecules. Persistent TGF-β1 activation and/or altered matrix biochemistry/biomechanics can lead to the activation of signaling pathways that promote both differentiation and inhibit apoptosis of myofibroblasts.
FIGURE 3.
FIGURE 3.
Therapeutic strategies to promote fibrosis resolution Strategies that may stimulate or accelerate the resolution of fibrosis may include the restoration of myofibroblast sensitivity to apoptosis, killing/elimination of senescent cells, disruption of collagen-matrix cross-links, augmentation of matrix proteolytic activity, and the clearance of degraded matrix molecules by cellular uptake and autophagy.
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