TNF-α Suppresses α-Smooth Muscle Actin Expression in Human Dermal Fibroblasts: An Implication for Abnormal Wound Healing

Goldberg, Mytien; Han, Yuan‐Ping; Yan, Chunli; Shaw, M.C.; Garner, W.L.

doi:10.1038/sj.jid.5700890

Cited by 176 publications

(150 citation statements)

References 39 publications

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“…Fibroblasts derived from surgical scar tissue produce high levels of α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β1 (7). TGF-β1 is one of the key cytokines in scar formation, and can act at different levels to increase collagen deposition.…”

Section: Introductionmentioning

confidence: 99%

Effects of CCN3 on fibroblast proliferation, apoptosis and extracellular matrix production

Ren

Hou

et al. 2014

International Journal of Molecular Medicine

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Abstract. CCN2 and CCN3 belong to the CCN family of proteins, which show a high level of structural similarity. Previous studies have shown that CCN2 mediates the ability of transforming growth factor (TGF)-β to stimulate collagen synthesis, leading to keloid formation. CCN2 and CCN3 are opposing factors in regulating the promoter activity and secretion of this extracellular matrix (ECM) protein. Thus, we hypothesize that CCN3 possesses an anti-scarring effect. However, the exact mechanism of CCN3 in this anti-scarring effect remains unclear. The aim of this study was to investigate the mechanism of CCN3 in reducing scar formation. Palatal fibroblasts were obtained from the explants of the oral palatal mucosa of 8-week-old male Sprague-Dawley rats. CCN3 overexpression vector was constructed and then transfected into cells. The inhibitory effects of CCN3 on cell growth were detected via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured using an Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) apoptosis detection kit and flow cytometry. The expression levels of collagen I, collagen III and α-smooth muscle actin (α-SMA) were determined by western blot analysis and RT-PCR. Following treatment with TGF-β1, we detected the expression of CCN3 and Smad1 in the fibroblasts. CCN3 significantly inhibited the growth and induction of apoptosis of fibroblasts. The expression of collagen I, collagen III and α-SMA was lower in the CCN3-transfected group as compared to the control and vector groups. TGF-β1 stimulation efficiently suppressed the expression of CCN3 at the mRNA and protein levels, and CCN3 was required for TGF-β1-induced Smad1 phosphorylation. Results of this study demonstrated that CCN3 is involved in the proliferation and apoptosis of fibroblasts and the synthesis of ECM proteins. Therefore, CCN3 may play an important role in the development of scar tissue, and may represent a novel therapeutic target for reducing scar formation.

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Section: Introductionmentioning

confidence: 99%

Effects of CCN3 on fibroblast proliferation, apoptosis and extracellular matrix production

Ren

Hou

et al. 2014

International Journal of Molecular Medicine

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“…The contractile force generated by myofibroblasts as a highly specialized cell, speeds the healing process of dermal wounds in healthy humans, accounting for 80-90 % of scar tissue reduction [117]. In diabetes, all the biological factors that instrument the onset of a contractile phenotype/ activity become reduced, which seems to be mostly attributed to the deleterious activities of TNF-α within the wound, thus suppressing α-SMA expression [118].…”

Section: The Diabetic Granulation Tissuementioning

confidence: 99%

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

Guillen-Nieto¹,

Herrera-Martínez²

2013

J Diabetes Metab

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T2DM is a heterogeneous group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Hyperglycemia may simply represent the tip of a broad series of molecular events from mitochondrial damages, to epigenetic and metabolic pathways deregulations. At the same time, hyperglycemia appears as the most proximal trigger for the onset and perpetual progression of multi-organ complications even under normoglycemic conditions. Thus, the initial hyperglycemic hit translates into a permanently harmful cellular imprinting as has been demonstrated in diabetic donors' cells after several passages and cultured in ideal conditions. The wound healing failure along with the inability of the innate immunity to control peripheral infections is the hybrid that determines that 85% of all non-traumatic lower extremity amputations are practiced in diabetic subjects. Diabetic wounds exhibit a complex networking of inflammatory cytokines, local proteases, cytotoxic reactive oxygen and nitrogen species and a polymicrobial biofilm that impose a stagnant phenotype. All these ingredients negatively impact on fibroblasts, endothelial cells and keratinocytes while paradoxically perpetuate the immuno-inflammatory infiltrate. Although the molecular fundamentals toward chronification have not been elucidated, it seems that different gene simultaneously converge to impose the wound cells a pro-senescent, pro-catabolic and pro-apoptotic phenotype given the lack of a "physiological tuning" of tyrosine kinase-dependent receptors due to their limited activation by insulin and local growth factors. Although recombinant growth factors and smart devices have been introduced during the last years the figures of amputations are still discouraging. Faults have been committed while selecting the appropriate growth factor and because of the "chronic" instinct to treat the chronic wounds topically, where bioavailability of the active principle is compromised by wound and bacterial biofilm proteases. The periodic intralesional infiltration of epidermal growth factor has proved to overcome this hurdle. Granulation tissue growth stimulation and wound healing capacity has been restored in diabetic patients by this procedure in several clinical trials and common clinical practice studies.

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“…The myofibroblasts are intermediate in nature between fibroblasts and smooth muscle cells, and thus are called "contracted cells" 3 3 -3 5 . The cells are identified immunocytochemically by detection of α-smooth muscle actin (α-SMA) 35,36 . Besides α-SMA, it is known that cytoskeletal features change in the development of myofibroblasts from stromal fibroblasts (Fig.…”

Section: Myofibroblastsmentioning

confidence: 99%

Heterogeneity of Macrophage Populations and Myofibroblasts Appearing in Rat Renal Interstitial Fibrosis

Yamate

2007

J Toxicol Pathol

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Macrophages and myofibroblasts play important roles in progressive renal fibrosis. Using cisplatin-induced rat renal fibrosis models, the author has investigated patho-biological characteristics of these cells. Macrophages seen in the fibrotic areas involve exudate macrophages, resident macrophages and antigen-presenting cells (activated dendritic cells and macrophages). In the early stages of renal fibrosis, exudate and resident macrophages are key cells for induction of myofibroblasts via producing fibrogenic factors such as transforming growth factor (TGF)-β1 and plateletderived growth factor (PDGF)-BB. In addition, these macrophages have capacity to phagocytize apoptotic bodies for clearance. [185][186][187][188][189][190][191][192][193][194][195]

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TNF-α Suppresses α-Smooth Muscle Actin Expression in Human Dermal Fibroblasts: An Implication for Abnormal Wound Healing

Cited by 176 publications

References 39 publications

Effects of CCN3 on fibroblast proliferation, apoptosis and extracellular matrix production

Effects of CCN3 on fibroblast proliferation, apoptosis and extracellular matrix production

Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

Heterogeneity of Macrophage Populations and Myofibroblasts Appearing in Rat Renal Interstitial Fibrosis

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