Activation of JNK Signaling Mediates Connective Tissue Growth Factor Expression and Scar Formation in Corneal Wound Healing

Shi, Long; Chang, Yuan; Yang, Yongmei; Zhang, Ying; Yu, Fei; Wu, Xinyi

doi:10.1371/journal.pone.0032128

Cited by 40 publications

(40 citation statements)

References 43 publications

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“…As previously described, VEGF and bFGF levels are closely correlated with neovascularization and fibroblast proliferation (5)(6)(7)(8). To further determine the association between MEBO and VEGF/bFGF, western blotting was used to determine the growth factor levels.…”

Section: Effects Of Mebo On the Protein Expression Of Vegf And Bfgfsupporting

confidence: 56%

“…Increasing evidence has established the hypothesis that growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are key regulators of normal and abnormal angiogenesis, and tissue repair in animals and humans (5)(6)(7)(8). VEGF promotes angiogenesis/vasculogenesis and vascular permeability, and enhances endothelial cell proliferation and migration as well as the adhesion of leukocytes (5,9).…”

Section: Introductionmentioning

confidence: 99%

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Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF

Tang

Han

Feng

et al. 2014

Molecular Medicine Reports

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Abstract. Cutaneous delayed wounds are a challenging clinical problem, and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) exhibit key roles in wound healing. Moist exposed burn ointment (MEBO), a Chinese burn ointment with a USA patented formulation, has been reported to promote chronic ischemic and neurogenic ulcer healing in patients; however, the underlying mechanisms remain unclear. In the present study, MEBO significantly promoted the formation of granulation tissue in cutaneous excisional wounds, shortened the time of wound healing, and increased neovascularization and the number of fibroblasts. Furthermore, as well as enhancing the protein expression, MEBO application also increased the gene expression of VEGF and bFGF. The results indicate that MEBO promotes cutaneous excisional wound healing by at least partially enhancing VEGF and bFGF production, implicating the potential uses of MEBO for delayed cutaneous wound healing. IntroductionCutaneous wounds, known as ulcers, are an extremely common clinical problem and often arise following acute or chronic mechanical causes, physical or chemical burns, frostbite, infections, and disorders, including rheumatism, diabetes, peripheral vascular disease, lipodermatosclerosis and malignant tumors (1,2). Furthermore, cutaneous wound healing may be significantly delayed due to the aforementioned factors. At present, delayed cutaneous wounds are one of major burdens for health care, and lead to a reduced quality of life in patients who suffer from this type of wound (3,4).Wound healing is a complicated biological process involving a series of dynamic events, including hemostasia, inflammation, cell proliferation and differentiation, neovascularization, granulation tissue formation, collagen synthesis, epithelialization, and wound contraction. Increasing evidence has established the hypothesis that growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are key regulators of normal and abnormal angiogenesis, and tissue repair in animals and humans (5-8). VEGF promotes angiogenesis/vasculogenesis and vascular permeability, and enhances endothelial cell proliferation and migration as well as the adhesion of leukocytes (5,9). Further research revealed that VEGF stimulates hydrogen sulfide synthesis and release from endothelial cells, thus leading to subsequent endothelial cell growth, migration and permeability, microvessel formation, and wound healing (10). In addition, VEGF promotes epithelialization and collagen deposition in the wound (11). FGF-2, known as bFGF, is a member of a large FGF family and induces angiogenesis, endothelial cell and fibroblast proliferation, and wound healing (12)(13)(14). Recent data indicated that bFGF-mediated angiogenesis refers to endothelial cell proliferation, migration and tube formation by activating c-Jun N-terminal kinase/stress-activated protein kinase signaling (15). Notably, the expression of VEGF and bFGF was increased following skin in...

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Section: Effects Of Mebo On the Protein Expression Of Vegf And Bfgfsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF

Tang

Han

Feng

et al. 2014

Molecular Medicine Reports

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“…The expression of a-SMA is associated with scar formation in the cornea, 1,17 and we found that the expression of palladin in both the diseased cornea and the wounded cornea tended to overlap with that of a-SMA. Transforming growth factor-b 40 and its signaling pathways, 41 including those mediated by the MAPKs ERK, p38, and JNK, also play an important role in the formation of corneal stromal scars. Consistent with these previous observations, we have now found that TGF-b stimulated the expression of both palladin and a-SMA in HCFs in a manner dependent in part on p38, ERK, and JNK signaling, Comparison of collagen gel diameter for cells incubated as in (A) for 4 days.…”

Section: Discussionmentioning

confidence: 99%

Coordinated Regulation of Palladin and α–Smooth Muscle Actin by Transforming Growth Factor–β in Human Corneal Fibroblasts

Morishige

Murata

Nakamura

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Morishige N, Murata S, Nakamura Y, et al. Coordinated regulation of palladin and a-smooth muscle actin by transforming growth factor-b in human corneal fibroblasts. Invest Ophthalmol Vis Sci. 2016;57:3360-3368. DOI:10.1167/iovs.15-18763 PURPOSE. To investigate the role of palladin in the cornea, we examined expression of this actin assembly-related protein in normal, diseased, or injured corneal tissue as well as in cultured corneal fibroblasts. METHODS.Expression of palladin and a-smooth muscle actin (a-SMA) in the rat cornea with an incision wound, in the normal and diseased human cornea, and in cultured human corneal fibroblasts was examined by immunofluorescence or immunoblot analysis.RESULTS. The expression of both palladin and a-SMA was detected at the lesion site during wound healing in the rat cornea. Whereas neither palladin nor a-SMA was detected in the normal human cornea, the colocalization of both proteins was detected in diseased human corneas with underlying conditions characterized by the presence of fibrosis. The expression of both palladin and a-SMA in cultured human corneal fibroblasts was increased by transforming growth factor-b (TGF-b) in a manner sensitive to inhibition by blockers of Smad or mitogen-activated protein kinase (MAPK) signaling. Finally, RNA interference-mediated depletion of palladin attenuated the TGF-b-induced upregulation of a-SMA expression in human corneal fibroblasts as well as TGF-b-induced collagen gel contraction mediated by these cells. CONCLUSIONS.Palladin is expressed in the rat and human cornea in association with scar formation. Expression of palladin in human corneal fibroblasts is increased by TGF-b in a manner dependent on Smad and MAPK signaling and is required for the TGF-b-induced upregulation of a-SMA.

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“…Pretreatment with 3 lM PD98059 decreased CTGF-induced CXCL8/IL-8 protein secretion to only 5135 ± 435 qg/ml. CTGF activates diverse cellular signaling, and MAPK activation such as that of JNK and ERK has been reported previously [16,31,[36][37][38][39]. To elucidate more clearly whether MAPKs are involved in the signaling pathways mediating CTGF-induced CXCL8/IL-8 secretion, we measured the phosphorylated form of each kinase in CTGF-stimulated monocytes.…”

Section: Activation Of Jnk and P38 Mapk Is Required For Ctgf-induced mentioning

confidence: 97%

Transcriptional and posttranscriptional regulation of CXCL8/IL-8 gene expression induced by connective tissue growth factor

et al. 2015

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Connective tissue growth factor (CTGF), a CCN family member, is a secreted protein regulating cellular functions, including fibrosis, apoptosis, adhesion, migration, differentiation, proliferation, angiogenesis, and chondrogenesis. CTGF increases proinflammatory factor production; however, inflammatory cytokine regulation by CTGF is poorly understood. The aim of this study was to identify novel biological functions and elucidate the functional mechanisms of CTGF. Specifically, the study focused on the ability of CTGF-primed monocytes to secrete interleukin 8 (CXCL8/IL-8) and determined the signaling pathways involved in CTGF-induced CXCL8/IL-8 gene regulation during inflammation. We transfected wild-type or mutant CXCL8/IL-8 promoter-derived luciferase reporter constructs into 293T cells to examine the effect of CTGF on the CXCL8/IL-8 promoter. The results showed that the activator protein-1 and nuclear factor κB binding sites of the CXCL8/IL-8 promoter are essential for CTGF-induced CXCL8/IL-8 transcription. Moreover, the CTGF-induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase, and extracellular signal-regulated kinase (ERK) is involved in this process. In addition, adenosine-uridine-rich elements (AREs) of the CXCL8/IL-8 3'-untranslated region (3'-UTR) reduce CXCL8/IL-8 mRNA stability. To investigate whether CTGF regulates CXCL8/IL-8 gene expression at the posttranscriptional level, we transfected 293 cells with serial luciferase constructs containing different segments of the CXCL8/IL-8 3'-UTR and then stimulated the cells with CTGF. The results suggested that CTGF stabilized luciferase mRNA and increased luciferase activity by regulating the CXCL8/IL-8 3'-UTR. Moreover, the p38 MAPK pathway may contribute to CTGF-induced CXCL8/IL-8 mRNA stabilization.

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Activation of JNK Signaling Mediates Connective Tissue Growth Factor Expression and Scar Formation in Corneal Wound Healing

Cited by 40 publications

References 43 publications

Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF

Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF

Coordinated Regulation of Palladin and α–Smooth Muscle Actin by Transforming Growth Factor–β in Human Corneal Fibroblasts

Transcriptional and posttranscriptional regulation of CXCL8/IL-8 gene expression induced by connective tissue growth factor

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