Selective reduction of fibrotic markers in repairing corneas of mice deficient in Smad3

Stramer, Brian; Austin, Jeffrey S.; Roberts, Anita B.; Fini, M. Elizabeth

doi:10.1002/jcp.20215

Cited by 27 publications

(28 citation statements)

References 38 publications

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“…2A,B). Fibrotic markers, such as a-smooth muscle actin that marks myofibroblasts, begin to be expressed in the corneal stroma ,7 days after injury (Stramer et al, 2005) and we found their expression to be maximal by 3 weeks. Therefore we collected corneas 3 weeks following chemical injury and stained using Fig.…”

Section: Mmp12 Protects Against Corneal Stromal Myofibroblast Transfomentioning

confidence: 52%

Protective effects of matrix metalloproteinase-12 following corneal injury

Chan

Bertrand

et al. 2013

Journal of Cell Science

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SummaryCorneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers a-smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of Mmp12 2/2 mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in Mmp12 2/2 corneas by confocal imaging. We determined that the altered dynamics were the result of an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration 6 days later, mediated by altered expression levels of chemokines CXCL1 and CCL2, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data show that MMP12 has a protective effect on corneal fibrosis during wound repair through regulation of immune cell infiltration and angiogenesis.

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Section: Mmp12 Protects Against Corneal Stromal Myofibroblast Transfomentioning

confidence: 52%

Protective effects of matrix metalloproteinase-12 following corneal injury

Chan

Bertrand

et al. 2013

Journal of Cell Science

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“…We used phalloidin staining to identify changes in filamentous actin stress fibers arrangement in ECs that is characteristic for active fibroblasts [19]. Upon TGF-β treatment, MS-1 cells reorganized their actin cytoskeleton to the long stress fibers that cross the cell body, as previously described [40].…”

Section: Discussionmentioning

confidence: 99%

“…Smads are one of the major downstream cytoplasmic mediators of TGF-β signaling in ECs [10-13]. The role of Smad3 in TGF-β-induced EndMT was also documented in different types of ECs, whereas the function of Smad2 in fibrosis induction in response to TGF-β is still not clear [10, 19]. …”

Section: Introductionmentioning

confidence: 99%

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition

Ambrožová

Fidlerova

Verescakova

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. Methods The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. Results OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. Conclusions The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. General significance These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.

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“…Fibrosis is only observed in corneal injuries that include rupture of the epithelial basement membrane and wounding of the stroma [116]. Similar to dermal repair in the skin, PDGF and TGF-β are pivotal mediators of the corneal fibrotic response [117]. Due to the angiogenic privilege, platelets as critical source of PDGF and TGF-β are virtually absent, although their accumulation around the limbal vessels after wounding has been reported [118].…”

Section: The Fibrotic Response In Corneal Repairmentioning

confidence: 99%

Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities

Bukowiecki

Hos

Cursiefen

et al. 2017

IJMS

140

136

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The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, but at the same time also enable rapid restoration of tissue integrity and organ-specific function. The easy accessibility makes the skin an attractive model system to study tissue damage and repair. Findings from skin research have contributed to unravelling novel fundamental principles in regenerative biology and the repair of other epithelial-mesenchymal tissues, such as the cornea. Following barrier disruption, the influx of inflammatory cells, myofibroblast differentiation, extracellular matrix synthesis and scar formation present parallel repair mechanisms in cornea and skin wound healing. Yet, capillary sprouting, while pivotal in proper skin wound healing, is a process that is rather associated with pathological repair of the cornea. Understanding the parallels and differences of the cellular and molecular networks that coordinate the wound healing response in skin and cornea are likely of mutual importance for both organs with regard to the development of regenerative therapies and understanding of the disease pathologies that affect epithelial-mesenchymal interactions. Here, we review the principal events in corneal wound healing and the mechanisms to restore corneal transparency and barrier function. We also refer to skin repair mechanisms and their potential implications for regenerative processes in the cornea.

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Selective reduction of fibrotic markers in repairing corneas of mice deficient in Smad3

Cited by 27 publications

References 38 publications

Protective effects of matrix metalloproteinase-12 following corneal injury

Protective effects of matrix metalloproteinase-12 following corneal injury

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition

Wound-Healing Studies in Cornea and Skin: Parallels, Differences and Opportunities

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