Acceleration of Palatal Wound Healing in Smad3-deficient Mice

2009 ◽  
Vol 88 (8) ◽  
pp. 757-761 ◽  
Author(s):  
K. Jinno ◽  
T. Takahashi ◽  
K. Tsuchida ◽  
E. Tanaka ◽  
K. Moriyama
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Complex Process ◽  
Dermal Cells ◽  
Macrophage Inflammatory Protein ◽  
Tgf Β1

Wound healing is a well-orchestrated complex process leading to the repair of injured tissues. It is suggested that transforming growth factor (TGF)-β/Smad3 signaling is involved in wound healing. The purpose of this study was to investigate the role of TGF-β/Smad3 signaling in palatal wound healing in Smad3-deficient (Smad3−/−) mice. Histological examination showed that wound closure was accelerated by the proliferation of epithelium and dermal cells in Smad3−/− mice compared with wild-type (WT) mice. Macrophage/monocyte infiltration at wounded regions in Smad3−/− mice was decreased in parallel with the diminished production of TGF-β1, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α compared with WT mice. Fibrocytes, expressing hematopoietic surface marker and fibroblast products, were recruited and produced α-smooth-muscle actin in WT mice, but were not observed in Smad3−/− mice. These results suggest that TGF-β/Smad3 signaling may play an important role in the regulation of palatal wound healing.

scholarly journals FAK Inhibition Attenuates Corneal Fibroblast Differentiation In Vitro

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1682
Author(s):  
Vincent Yeung ◽  
Sriniwas Sriram ◽  
Jennifer A. Tran ◽  
Xiaoqing Guo ◽  
Audrey E. K. Hutcheon ◽  
...  
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Myofibroblast Differentiation ◽  
Corneal Scarring ◽  
Corneal Fibroblast ◽  
Corneal Fibroblasts ◽  
Corneal Wound ◽  
Tgf Β1

Corneal fibrosis (or scarring) occurs in response to ocular trauma or infection, and by reducing corneal transparency, it can lead to visual impairment and blindness. Studies highlight important roles for transforming growth factor (TGF)-β1 and -β3 as modulators in corneal wound healing and fibrosis, leading to increased extracellular matrix (ECM) components and expression of α-smooth muscle actin (αSMA), a myofibroblast marker. In this study, human corneal fibroblasts (hCF) were cultured as a monolayer culture (2D) or on poly-transwell membranes to generate corneal stromal constructs (3D) that were treated with TGF-β1, TGF-β3, or TGF-β1 + FAK inhibitor (FAKi). Results show that hCF 3D constructs treated with TGF-β1 or TGF-β3 impart distinct effects on genes involved in wound healing and fibrosis—ITGAV, ITGB1, SRC and ACTA2. Notably, in the 3D construct model, TGF-β1 enhanced αSMA and focal adhesion kinase (FAK) protein expression, whereas TGF-β3 did not. In addition, in both the hCF 2D cell and 3D construct models, we found that TGF-β1 + FAKi attenuated TGF-β1-mediated myofibroblast differentiation, as shown by abrogated αSMA expression. This study concludes that FAK signaling is important for the onset of TGF-β1-mediated myofibroblast differentiation, and FAK inhibition may provide a novel beneficial therapeutic avenue to reduce corneal scarring.

scholarly journals MCP-1, not MIP-1α, Is the Endogenous Chemokine That Cooperates With TGF-β to Inhibit the Cycling of Primitive Normal but not Leukemic (CML) Progenitors in Long-Term Human Marrow Cultures

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2338-2344 ◽  
Author(s):  
J.D. Cashman ◽  
C.J. Eaves ◽  
A.H. Sarris ◽  
A.C. Eaves
Keyword(s):  
Inhibitory Activity ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Progenitor Cell Proliferation ◽  
Normal Human ◽  
Macrophage Inflammatory Protein

Abstract The long-term culture (LTC) system has been useful for analyzing mechanisms by which stromal cells regulate the proliferative activity of primitive normal, but not chronic myeloid leukemia (CML), hematopoietic progenitor cells. In previous studies, we identified two endogenous inhibitors in this system. One is transforming growth factor-β (TGF-β), which is equally active on primitive normal and CML progenitors. The other we now show to be monocyte chemoattractant protein-1 (MCP-1). Thus, MCP-1, when added to LTC, blocked the activation of primitive normal progenitors but did not arrest the cycling of primitive CML progenitors. Moreover, the endogenous inhibitory activity of LTC stromal layers could be overcome by the addition of neutralizing antibodies to MCP-1, but not to macrophage inflammatory protein-1α (MIP-1α). However, neither of these antibodies antagonized the inhibitory activity of NAc-Ser-Asp-Lys-Pro (AcSDKP) on primitive normal but not CML progenitor cycling in this system. Moreover, none of six other -C-C- or -C-X-C- chemokines, previously shown to inhibit primitive normal human CFC proliferation in semisolid assays, were found to act as negative regulators when added to normal LTC. These results provide further support for the concept that primitive CML progenitor cell proliferation is deregulated when these cells are exposed to limiting concentrations of multiple inhibitors, only some of which have differential actions on normal and Ph+/BCR-ABL+ cells.

scholarly journals Macrophage Inflammatory Protein 1α/CCL3 Is Required for Clearance of an Acute Klebsiella pneumoniae Pulmonary Infection

2001 ◽  
Vol 69 (10) ◽  
pp. 6364-6369 ◽  
Author(s):  
Dennis M. Lindell ◽  
Theodore J. Standiford ◽  
Peter Mancuso ◽  
Zachary J. Leshen ◽  
Gary B. Huffnagle
Keyword(s):  
Klebsiella Pneumoniae ◽  
Alveolar Macrophages ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Cytokine Levels ◽  
Factor Alpha ◽  
Macrophage Inflammatory Protein

ABSTRACT The objective of these studies was to determine the role of macrophage inflammatory protein 1α/CCL3 in pulmonary host defense during Klebsiella pneumoniae infection. Following intratracheal inoculation, 7-day survival of CCL3−/− mice was less than 10%, compared to 60% for CCL3+/+ mice. Survival of CCR5−/− mice was equivalent to that of controls, indicating that the enhanced susceptibility of CCL3−/− mice to K. pneumoniae is mediated via another CCL3 receptor, presumably CCR1. At day 3, CFU burden in the lungs of CCL3−/− mice was 800-fold higher than in CCL3+/+ mice, demonstrating that CCL3 is critical for control of bacterial growth in the lung. Surprisingly, CCL3−/− mice had no differences in the recruitment of monocytes/macrophages and even showed enhanced neutrophil recruitment at days 1, 2, and 3 postinfection, compared to CCL3+/+ mice. Therefore, the defect in clearance was not due to insufficient recruitment of leukocytes. No significant differences in cytokine levels of monocyte chemoattractant protein 1 (MCP-1), interleukin 12, gamma interferon, or tumor necrosis factor alpha in lung lavages were found between CCL3+/+ and CCL3−/− mice. CCL3−/− alveolar macrophages were found to have significantly lower phagocytic activity toward K. pneumoniae than CCL3+/+alveolar macrophages. These findings demonstrate that CCL3 production is critical for activation of alveolar macrophages to control the pulmonary growth of the gram-negative bacterium K. pneumoniae.

scholarly journals MCP-1, not MIP-1α, Is the Endogenous Chemokine That Cooperates With TGF-β to Inhibit the Cycling of Primitive Normal but not Leukemic (CML) Progenitors in Long-Term Human Marrow Cultures

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2338-2344 ◽  
Author(s):  
J.D. Cashman ◽  
C.J. Eaves ◽  
A.H. Sarris ◽  
A.C. Eaves
Keyword(s):  
Inhibitory Activity ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Monocyte Chemoattractant Protein 1 ◽  
Inflammatory Protein ◽  
Progenitor Cell Proliferation ◽  
Normal Human ◽  
Macrophage Inflammatory Protein

The long-term culture (LTC) system has been useful for analyzing mechanisms by which stromal cells regulate the proliferative activity of primitive normal, but not chronic myeloid leukemia (CML), hematopoietic progenitor cells. In previous studies, we identified two endogenous inhibitors in this system. One is transforming growth factor-β (TGF-β), which is equally active on primitive normal and CML progenitors. The other we now show to be monocyte chemoattractant protein-1 (MCP-1). Thus, MCP-1, when added to LTC, blocked the activation of primitive normal progenitors but did not arrest the cycling of primitive CML progenitors. Moreover, the endogenous inhibitory activity of LTC stromal layers could be overcome by the addition of neutralizing antibodies to MCP-1, but not to macrophage inflammatory protein-1α (MIP-1α). However, neither of these antibodies antagonized the inhibitory activity of NAc-Ser-Asp-Lys-Pro (AcSDKP) on primitive normal but not CML progenitor cycling in this system. Moreover, none of six other -C-C- or -C-X-C- chemokines, previously shown to inhibit primitive normal human CFC proliferation in semisolid assays, were found to act as negative regulators when added to normal LTC. These results provide further support for the concept that primitive CML progenitor cell proliferation is deregulated when these cells are exposed to limiting concentrations of multiple inhibitors, only some of which have differential actions on normal and Ph+/BCR-ABL+ cells.

scholarly journals A mathematical model of wound healing and subsequent scarring

2009 ◽  
Vol 7 (42) ◽  
pp. 19-34 ◽  
Author(s):  
B. D. Cumming ◽  
D. L. S. McElwain ◽  
Z. Upton
Keyword(s):  
Wound Healing ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dermal Wound Healing ◽  
Hybrid Approaches ◽  
Complex Process ◽  
Representation Techniques ◽  
Dermal Wound ◽  
Size Scales

Wound healing is a complex process involving the delicate interaction between elements that vary widely in nature and size scales, from the nanometre level, such as molecules, to cells measured in micrometres, and fibres with width and length measured on both scales. Hybrid approaches, where each species is represented by a model on an appropriate size scale, have received attention recently. In this study, we provide a review of earlier work on such hybrid models of wound healing. General models for each of the element types involved in dermal wound healing used in this research are described: cells, modelled as discrete individuals; chemicals, modelled as continua; and fibres, modelled with a novel tensorial representation. Techniques for integrating such disparate models are outlined. A six-species model (fibrin, collagen, macrophages, fibroblasts, transforming growth factor-β (TGF-β) and tissue plasminogen activator) of dermal wound healing is presented. The role of the cytokine TGF-β in the healing cascade is investigated using the model, along with its role in the degree of scarring in the healed tissue.

scholarly journals MCP-1/CCR2 system is involved in high glucose-induced fibronectin and type IV collagen expression in cultured mesangial cells

2008 ◽  
Vol 295 (3) ◽  
pp. F749-F757 ◽  
Author(s):  
Jehyun Park ◽  
Dong-Ryeol Ryu ◽  
Jin Ji Li ◽  
Dong-Sub Jung ◽  
Seung-Jae Kwak ◽  
...  
Keyword(s):  
Protein Expression ◽  
High Glucose ◽  
Type Iv Collagen ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Type Iv ◽  
Ccr2 Expression ◽  
Tgf Β1

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that plays an important role in the recruitment of macrophages. Although previous studies have demonstrated the importance of MCP-1 in the pathogenesis of diabetic nephropathy (DN) in terms of inflammation, the role of MCP-1 and its receptor (C-C chemokine receptor 2; CCR2) in extracellular matrix (ECM) accumulation under diabetic conditions has been largely unexplored. This study was undertaken to investigate the functional role of the MCP-1/CCR2 system in high glucose-induced ECM (fibronectin and type IV collagen) protein expression in cultured mesangial cells (MCs). Mouse MCs were exposed to medium containing 5.6 mM glucose (NG), NG+24.4 mM mannitol (NG+M), or 30 mM glucose (HG) with or without mutant MCP-1 (mMCP-1), CCR2 small interfering (si)RNA, or CCR2 inhibitor (RS102895). To examine the relationship between MCP-1 and transforming growth factor (TGF)-β1, MCs were also treated with TGF-β1 (2 ng/ml) with or without mMCP-1 or CCR2 siRNA. Transient transfection was performed with Lipofectamine 2000 for 24 h. Cell viability was determined by an MTT assay, mouse and human MCP-1 and TGF-β1 levels by ELISA, and CCR2 and ECM protein expression by Western blotting. Transfections of mMCP-1 and CCR2 siRNA increased human MCP-1 levels and inhibited CCR2 expression, respectively. HG-induced ECM protein expression and TGF-β1 levels were significantly attenuated by mMCP-1, CCR2 siRNA, and RS102895 ( P < 0.05). MCP-1 directly increased ECM protein expression, and this increase was inhibited by an anti-TGF-β1 antibody. In addition, TGF-β1-induced ECM protein expression was significantly abrogated by the inhibition of the MCP-1/CCR2 system ( P < 0.05). These results suggest that an interaction between the MCP-1/CCR2 system and TGF-β1 may contribute to ECM accumulation in DN.

scholarly journals Delayed administration of suramin attenuates peritoneal fibrosis in rats

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Chongxiang Xiong ◽  
Na Liu ◽  
Xiaofei Shao ◽  
Sairah Sharif ◽  
Hequn Zou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Effective Treatment ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Interleukin 1 ◽  
Growth Factor Receptor ◽  
Peritoneal Fibrosis ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tgf Β1

Abstract Background Peritoneal fibrosis is the most common complication of peritoneal dialysis, but there is currently no effective treatment. We previously reported that suramin pretreatment prevents the development of peritoneal fibrosis in a rat model of peritoneal fibrosis induced by chlorhexidine gluconate (CG). Here, we further examined the effectiveness of delayed administration of suramin on peritoneal fibrosis and the mechanism (s) involved in this process. Methods In the rat model of peritoneal fibrosis induced by CG, suramin or saline was administered at day 21 and 28. All rats were then sacrificed to collect peritoneal tissues for Western blot analysis and histological staining at day 35. Results Our results demonstrated that delayed administration of suramin starting at 21 days following CG injection can ameliorate peritoneal damage, with greater efficacy after two injections. Suramin also reduced the expression of α-smooth muscle actin, Collagen 1, and Fibronectin and suppressed phosphorylation of Smad-3, epidermal growth factor receptor (EGFR), signal transducers, activator of transcription 3 (STAT3) as well as extracellular signal-regulated kinases 1/2 (ERK 1/2) in the peritoneum injured with CG. Moreover, delayed administration of suramin inhibited overproduction of transforming growth factor-β1(TGF-β1) and expression of several pro-inflammatory cytokines, including monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-1, and interleukin-6. Conclusions Our results indicated that suramin can attenuate progression of peritoneal fibrosis by a mechanism involving inhibition of the TGF-β1/Smad3 and EGFR signaling pathways as well as suppression of multiple proinflammatory cytokines. Thus, suramin may have the potential to offer an effective treatment for peritoneal fibrosis.

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