Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation

Macarak, Edward J.; Lotto, Christine E.; Koganti, Deepika; Jin, Xiaodong; Wermuth, Peter J.; Olsson, Anna-Karin; Montgomery, Matthew; Rosenbloom, Joel

doi:10.1016/j.jss.2018.02.012

Cited by 17 publications

(10 citation statements)

References 56 publications

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“…JUN signals via several known fibrosis-related pathways, including VEGF , FGFR , PDGFR , and TGFBR 6 . Inhibitors of these well-known, downstream, fibrosis-associated pathways have shown some effect at modulating adhesion formation in mice, for example the MEK inhibitor trametinib 7 , but it has remained unknown what the upstream transcriptional regulator of adhesion pathology might be. Furthermore, abdominal adhesion fibroblasts have yet to be characterized at the single-cell level to appreciate the functional heterogeneity involved.…”

Section: Introductionmentioning

confidence: 99%

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

et al. 2020

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Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti- JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.

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Section: Introductionmentioning

confidence: 99%

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

et al. 2020

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“…Indeed, a recent study that examined mesenchymal cell phenotypes present in the normal and fibrotic lungs of mice identified six distinct subpopulations in normal lungs and seven distinct subpopulations in fibrotic lungs [45]. In agreement with these observations, other studies have shown that during the wound healing process, some populations of fibroblasts display certain features characteristic of activated myofibroblasts, such as increased synthesis of ECM macromolecules but remarkably, lack other important features such as α-SMA expression [46, 47].…”

Section: Introductionmentioning

confidence: 60%

Abrogation of transforming growth factor-β-induced tissue fibrosis in mice with a global genetic deletion of Nox4

Wermuth

Mendoza

Jimenez

2019

Laboratory Investigation

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Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF-β plays a crucial role in SSc pathogenesis. The expression of NADPH oxidase 4 (NOX4), a critical mediator of oxidative stress, is potently stimulated by TGF-β. Here, we evaluated the effect of NOX4 on the development of TGF-β-induced tissue fibrosis. C57BL6/J control mice and Nox4 knockout mice were implanted subcutaneously with osmotic pumps containing either saline or 2.5 μg TGF-β1. After 28 days, skin and lung samples were isolated for histopathologic analysis, measurement of hydroxyproline content and gene expression analysis. Histopathology of skin and lungs from normal C57BL6/J mice treated with TGF-β1 showed profound dermal fibrosis and peribronchial and diffuse interstitial lung fibrosis. In contrast, TGF-β-treated Nox4 knockout mice showed normal skin and lung histology. Hydroxyproline levels in TGF-β-treated C57BL6/J mice skin and lungs demonstrated significant increases, however, hydroxyproline content of TGF-β-treated Nox4 knockout mice tissues was not changed. Expression of various profibrotic and fibrosis-associated genes was upregulated in skin and lungs of TGF-β1-treated C57BL6/J mice but was not significantly changed in TGF-β1-treated Nox4 knockout mice. The induction of skin and lung tissue fibrosis by TGF-β1 parenteral administration in mice was abrogated by the genetic deletion of Nox4 confirming that NOX4 is an essential mediator of the profibrotic effects of TGF-β. These results suggest Nox4 inhibition as a potential therapeutic target for SSc and other fibroproliferative disorders.

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“…[ 263 ] or Macarak et al. [ 264 ] The mouse models were preferred for the evaluation of drugs. Due to body size, abrasion only models were mainly reported.…”

Section: Animal Modelsmentioning

confidence: 99%

Advancement of Biomaterial‐Based Postoperative Adhesion Barriers

Chandel

Shimizu

Hasegawa

et al. 2021

Macromolecular Bioscience

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Postoperative peritoneal adhesion (PPA) is a prevalent incidence that generally happens during the healing process of traumatized tissues. It causes multiple severe complications such as intestinal obstruction, chronic abdominal pain, and female infertility. To prevent PPA, several antiadhesion materials and drug delivery systems composed of biomaterials are used clinically, and clinical antiadhesive is one of the important applications nowadays. In addition to several commercially available materials, like film, spray, injectable hydrogel, powder, or solution type have been energetically studied based on natural and synthetic biomaterials such as alginate, hyaluronan, cellulose, starch, chondroitin sulfate, polyethylene glycol, polylactic acid, etc. Moreover, many kinds of animal adhesion models, such as cecum abrasion models and unitary horn models, are developed to evaluate new materials’ efficacy. A new animal adhesion model based on hepatectomy and conventional animal adhesion models is recently developed and a new adhesion barrier by this new model is also developed. In summary, many kinds of materials and animal models are studied; thus, it is quite important to overview this field's current progress. Here, PPA is reviewed in terms of the species of biomaterials and animal models and several problems to be solved to develop better antiadhesion materials in the future are discussed.

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Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion formation

Cited by 17 publications

References 56 publications

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

Abrogation of transforming growth factor-β-induced tissue fibrosis in mice with a global genetic deletion of Nox4

Advancement of Biomaterial‐Based Postoperative Adhesion Barriers

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