You Say You Want a Resolution (of Fibrosis)

Abstract

In pathological fibrosis, aberrant tissue remodeling with excess extracellular matrix leads to organ dysfunction and eventual morbidity. Diseases of fibrosis create significant global health and economic burdens and are often deadly. Although fibrosis has traditionally been thought of as an irreversible process, a growing body of evidence demonstrates that organ fibrosis can reverse in certain circumstances, especially if an underlying cause of injury can be removed. This body of evidence has uncovered more and more contributors to persistent and nonresolving tissue fibrosis. Here, we review the present knowledge on resolution of organ fibrosis and restoration of near-normal tissue architecture. We emphasize three critical areas of tissue homeostasis that are necessary for fibrosis resolution, namely, the elimination of matrix-producing cells, the clearance of excess matrix, and the regeneration of normal tissue constituents. In so doing, we also highlight how profibrotic pathways interact with one another and where there may be therapeutic opportunities to intervene and remediate pathological persistent fibrosis.

Keywords: extracellular matrix turnover; fibroblasts; fibrosis; pulmonary fibrosis; resolution of fibrosis.

Figure 1.

Schematic representation of the cellular events leading to pathological persistence of fibroblasts. This overview of the activation and persistence of fibroblasts in pathological fibrosis highlights the distinct mechanisms that drive tissue fibrosis. In normal physiological conditions, the secretion of profibrotic cytokines drives fibroblast activation and matrix production. Activated fibroblasts are primed for cell death and either dedifferentiate via transcriptional control of profibrotic genes or undergo apoptosis. In pathological fibrosis, the fibrotic milieu persists as activated fibroblasts bypass inactivation pathways by way of aberrant activation of profibrotic signaling, inhibition of antifibrotic molecules, and stiff matrix–induced feed-forward loops. AMPK = 5′ AMP-activated protein kinase; BCL2 = B cell lymphoma-2; PPAR-γ = peroxisome proliferator–activated receptor γ; MyoD = myoblast determination protein 1; Nrf2 = nuclear factor erythroid 2–related factor 2; PDGF = platelet-derived growth factor; TAZ = transcriptional coactivator with PDZ binding motif; TGF-β1 = transforming growth factor-β1; Thy1 = thymocyte differentiation antigen 1; YAP = yes-associated protein 1.

Figure 2.

Collagen degradation and internalization are mediated by several pathways. Collagen fibrils are cleaved 1) in the extracellular space and 2) at the cell surface. The resulting fragments are internalized through 3) macropinocytotic, 4) phagocytic, and 5) endocytic pathways and are ultimately degraded by the lysosome. 1) Extracellular proteolysis of collagen fibrils. 2) Cell-surface degradation of collagen fibrils. 3) Nonselective actin-dependent micropinocytosis. 4) Integrin α2β1–mediated phagocytosis. 5) Opsonization and cellular uptake of collagen fragments. 6) Cell-mediated endocytosis of collagen fragments. ApoE = apolipoprotein E; BECN1 = beclin 1; FAP = fibroblast activation protein; LRP1 = LDL receptor related protein 1; MFGE8 = milk fat globule-epidermal growth factor 8 protein; MMP = matrix metalloproteinase; MRC2 = mannose receptor C type 2.

Figure 3.

Profibrotic feed-forward mechanisms of nonresolving fibrosis. Positive feed-forward loops are associated with the fibrotic matrix that sustain and amplify the fibrotic phenotype. 1) Stiff and fibrotic extracellular matrix signals impair normal fibroblast apoptosis and differentiation and lead to persistent expression of profibrotic genes that contribute to increased matrix stiffness. 2) These cues also compromise normal epithelial function and tissue regeneration, leading to dysfunctional TGF-β1 activity and amplified extracellular matrix deposition. 3) Enzymatic cross-linking of persistent fibrotic matrix further exacerbates the aberrant mechanical milieu by physically impeding the collagen degradative machinery. ECM = extracellular matrix; ER = endoplasmic reticulum; LOX = lysyl oxidase; miR-29 = microRNA 29; TBK1 = tank-binding kinase 1; tTG = tissue transglutaminase; UPR = unfolded protein response.