Mechanisms of tissue repair: from wound healing to fibrosis

Mutsaers, Steven E.; Bishop, June E.; McGrouther, Gus; Laurent, Geoffrey J.

doi:10.1016/s1357-2725(96)00115-x

Cited by 399 publications

(304 citation statements)

References 64 publications

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“…The pathogenesis of progressive tissue fibrosis is incompletely understood, but has been likened to an exuberant and dysregulated wound-healing response (22). Therefore, understanding the means by which tissue injury is limited and normal wound healing is triggered is of critical importance.…”

Section: Discussionmentioning

confidence: 99%

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Muro¹,

Moretti²,

Moore³

et al. 2008

Am J Respir Crit Care Med

258

253

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Rationale: Tissue fibrosis is considered a dysregulated wound-healing response. Fibronectin containing extra type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen. Objectives: To investigate the role of EDA-containing fibronectin in lung fibrogenesis. Methods: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and a-smooth muscle actin (a-SMA) expression. Mice lacking the EDA domain of fibronectin and their wild-type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes. Measurements and Main Results: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and a-SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days after bleomycin challenge, whereas wildtype controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer a-SMA-expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-b and decreased lung fibroblast responsiveness to active TGF-b in vitro. Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-b activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.Keywords: fibrosis; fibronectin; TGF-b; myofibroblast Fibroproliferative disorders, characterized by the increased production and deposition of extracellular matrix (ECM) proteins in tissues, are not well understood despite major efforts to elucidate pathogenic mechanisms. Recent attention has focused on ECM components and mesenchymal cell phenotypes as being critical to the development of fibrosis (1, 2). The ECM is a highly dynamic complex that varies in composition according to its tissue localization and physiologic circumstances. Collagens are the predominant ECM proteins identified in fibrotic lesions and are the hallmark of fibroproliferative diseases, but fibronectins (FNs) are also present in abnormally large quantities and localize to areas of active fibrogenesis (3, 4).FNs are multifunctional glycoproteins found in the ECM of tissues and plasma. Two main forms of FN exist: plasma FN, a dimeric and soluble form produced by hepatocytes that lacks the EDA and EDB sequences, and cellular FN (cFN), a multimeric form synthesized by mesenchymal, epithelial, and inflammatory cells, which is deposited in ECM fibrils and that contains variable proportions of the extra type III domains A and B (EDA and EDB) (5...

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Section: Discussionmentioning

confidence: 99%

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Muro¹,

Moretti²,

Moore³

et al. 2008

Am J Respir Crit Care Med

258

253

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“…During inflammation, growth factors and cytokines stimulate fibroblasts to form scar tissue. 18 The restoration of normal tissue homeostasis by the replacement of scar tissue with healthy tissue requires the induction of apoptosis and the subsequent clearance of apoptotic fibroblasts. Despite the obvious importance of this process to normal tissue homeostasis and the prevention of fibrosis, the mechanisms involved in the recruitment of macrophages and their recognition of apoptotic fibroblasts has not been previously addressed.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, TSP1 has been implicated in adhesion between platelets and monocyte by forming molecular bridges with CD36 and other integrin receptors. 18 Lawler and colleagues 30 demonstrated patchy fibroblastic foci in the lungs of TSP1-deficient mice and suggested that might in part be because of the impaired phagocytosis of apoptotic cells because the TSP1-bridging molecule between the apoptotic cell and phagocyte is absent. Thus it is feasible that the absence of TSP1 may adversely affect phagocyte recognition and subsequent engulfment of the apoptotic cell.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Recognition and Phagocytosis of Apoptotic Fibroblasts Is Critically Dependent on Fibroblast-Derived Thrombospondin 1 and CD36

Moodley

Rigby

Bundell

et al. 2003

The American Journal of Pathology

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The induction of fibroblast apoptosis and their clearance by phagocytes is essential for normal wound healing and prevention of scarring. However, little is known about the clearance of apoptotic fibroblasts and whether apoptotic cells are active participants in the recruitment and activation of phagocytes. In this study, we provide the first evidence that apoptotic fibroblasts actively release increased amounts of thrombospondin (TSP1) to actively recruit macrophages. Expression of TSP1 and its receptor CD36 was increased on the surface of apoptotic fibroblasts. By chemical cross-linking and immunoprecipitation we show that TSP1 and CD36 were directly associated. This was confirmed by confocal microscopy. Blockade of either CD36 or TSP1 on apoptotic fibroblasts inhibited phagocytosis. Blockade of ␣v␤3 integrins as well as CD36 and TSP1 on macrophages inhibited phagocytosis. In contrast, phosphatidylserine or lectins were not involved. These findings suggest that apoptotic fibroblasts release TSP1 as a signal to recruit macrophages while the up-regulated expression of the CD36/TSP1 complex on their cell surface may form a ligand bridging the fibroblast to a complex consisting of ␣v␤3/CD36/TSP1 on macrophages.

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“…Fibroblasts can produce a large amount of collagen protein to increase the overall tissue tensile strength that contributes to vascular stiffening and impaired function [8]. The presence of differentiated contractile myofibroblast has been associated with the increase of ECM stiffness and they mediate the production of force for wound contraction [9]. The interaction between fibroblasts and various ECM components has been investigated using a number of engineering tools.…”

Section: Introductionmentioning

confidence: 99%

Collagen matrix stiffness influences fibroblast contraction force

Jin¹,

Li²,

Siow³

et al. 2016

Biomed. Phys. Eng. Express

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Abstract. Cell-embedded hydrogel has been widely used as engineered tissue equivalents in biomedical applications. In this study, contraction force in human aortic adventitial fibroblasts seeded within a 3D collagen matrix was quantified by a novel force sensing technique. We demonstrate that contraction forces in cells treated with histamine are regulated by the gel stiffness in a linear manner.These findings provide novel insights for the design of collagen-based biomaterials for tissue engineering and clinical applications.

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Mechanisms of tissue repair: from wound healing to fibrosis

Cited by 399 publications

References 64 publications

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Macrophage Recognition and Phagocytosis of Apoptotic Fibroblasts Is Critically Dependent on Fibroblast-Derived Thrombospondin 1 and CD36

Collagen matrix stiffness influences fibroblast contraction force

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