FGF-9 overexpression prevents pleural fibrosis induced by intra-pleural adenovirus injection in mice
A. JustetAudrey JoannesJ. Marchal-SomméValérie BesnardPhilippe BonniaudArnaud MailleuxBruno Crestani
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Introduction: Lung fibrosis is associated with the reactivation of molecular pathways involved in lung development. Mesothelial cells are involved in the fibrotic lung process but their exact role is debated. Fibroblast Growth Factor-9 (FGF-9) is expressed by epithelial cells and visceral pleura during embryonic lung development. Mice homozygous for a targeted disruption of FGF-9 exhibit lung hypoplasia with reduced mesenchyme and early postnatal death. The aim of this study was to evaluate the role of FGF-9 expression by mesothelial cells in the adult lung. We used adenovirus-mediated (FGF-9) gene transfer in mesothelial cells in vivo. Material and Methods: AdFGF9 or a control adenovirus (AdCont) (108pfu/mL) was administered in 100 μl of 0.9% NaCl by pleural injection of C56/Bl6 male mice. Mice were studied at day 3, day 5, and day 14.We quantified FGF-9 in pleural fluid by ELISA. The expression of FGF-9, inflammation and pro fibrotic markers were assessed by qPCR, and immunochemistry. Results: Intrapleural injection of AdCont led to pleural inflammation and pleural remodeling beginning at day 5 and maximal at day 14, with pleural thickening, and accumulation of α-SMA+ cells and collagen. AdCont induced murine FGF-9 expression in the pleura. AdFGF-9 led to human FGF-9 overexpression in the pleural fluid and in the lung at day 5. AdFGF-9 completely inhibited the development of pleural remodeling, with a significant decrease of Collagen I, III, fibronectin, PAI-1, CTGF mRNA expression. Conclusion: Intrapleural injection of adenovirus induces pleural fibrosis. It is prevented by pleural overexpression of human FGF-9 suggesting that mesothelial FGF-9 has anti fibrotic properties.Keywords:
Immunochemistry
Mesenchyme
瞄准：检验结缔组织生长因素(CTGF ) 的表示，也作为 CCN2 知道在胃的癌(GC ) ，并且在 CTGF，临床病理特征和有 GC 的病人的临床的结果的表示之间的关联。方法：122 个 GC 病人在现在的学习被包括。所有病人被跟随在上面为至少 5 年。CTGF 的蛋白质用染色方法的 Powervision 二拍子的圆舞免疫被检测。结果：从为 CTGF 表示分析的 122 个 GC 病人的标本， 58 (58/122， 47.5%) 在胃的癌房间的细胞质有高 CTGF 表情并且 64 (64/122， 52.5%) 有低 CTGF 表情。有高 CTGF 表情的病人与低 CTGF 表情比那些显示出淋巴节点转移的更高的发生(P = 0.032 ) 。有有的高 CTGF 表情的病人显著地与低 CTGF 表情比那些降低 5 年的幸存率(27.6% 对 46.9% ， P = 0.0178 ) ，特别那些阶段我 +II + III (35.7% 对 65.2% ， P = 0.0027 ) 。结论：有提高的 CTGF 表情的 GC 病人有更多的淋巴节点转移和更短的生存时间。CTGF 似乎是为高风险的 GC 病人阶段的成功的区别的一个独立预示的因素我 +II + III。在人的 GC 房间的 CTGF 的在表示上导致一个增加的好攻击的能力。
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Objective To investigate the effect of Astragalus on the expression of connective tissue growth factor(CTGF)protein and CTGF mRNA in kidney tissues of rats with diabetic nephropathy.Methods Rat model with diabetic nephropathy was established by unilateral nephrectomy,high-carbonhydrate and high fat diet and intraperitoneal injection of streptozotocin(STZ).The rats were randomly divided into 4 groups that is sham-operation group,model group,Astragalus treated group and irbesatan(IRB)treated group.Animals were sacrified at 12 weeks.Pathological examination of renal tissues was carried out.The expression of CTGF protein in renal tissues was detected by immunohistochemistry assay.The expression of CTGF mRNA was measured by reverse transcription polymerase chain reaction(RT-PCR).Results Compared with sham-operation group the expression of CTGF and CTGF mRNA were increased significantly in renal tissues of model group(P0.01).However,the expression of CTGF and CTGF mRNA in Astragalus treated group were significantly decreased in comparison with model group(P0.05).Conclusion Astragalus could be used to treat diabetic nephropathy and the mechanism may be related to down-regulating the expression of CTGF protein and CTGF mRNA.
Astragalus
Intraperitoneal injection
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Objective To investigate the expression of connective tissue growth factor (CTGF) in kidney tissues and its relationship with kidney fibrosis in lupus nephritis (LN).Methods CTGF of 36 specimens from LN kidneys and 15 from normal controls were detected by immunohistochemistry and hybridization in situ in order to find out the relationship of CTGF expression with fibrosis of kidney interstitium.Results CTGF distributed not only on tubular epithelial cells and interstitial cells,but also on glomerular epithelial cells and mesangial cells in LN.There was no or only a little renal CTGF mRNA and protein expression in normal controls.Renal CTGF mRNA and protein expression was significantly higher than normal controls(CTGF mRNA: 8.22±3.13 to 1.12±0.23; CTGF protein: 8.74±3.24 to 1.21±0.22,P0.001);Renal CTGF expression in LN was positively related with tubulointerstitial fibrosis(r=0.863,P0.01).Renal CTGF expression in type Ⅳ LN was significantly higher than in other LN(CTGF mRNA: 10.73±3.61 to 4.78±1.82,CTGF protein: 11.03±1.12 to 5.02±1.31 P0.01).Renal CTGF protein expression was also positively related with TGF-β1,FN and ColIII(r=0.704?r=0.783 and r=0.756,P0.01) in LN.Conclusion The level of renal CTGF mRNA and protein expression is gradually increased with the degree of tubulointerstitial fibrosis.As the downstream factor of TGF-β,CTGF may promote the expansion of extra-matrix such as Fn and ColIII,and enhance the glomerular and tubulointerstitial fibrosis in LN.
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The migratory mesenchymal cells in cultures of the embryonic chick heart show all stages of transformation from the bipolar and multipolar reticular cells to the flat mesothelial forms. One can actually observe this change in form. Such mesothelial cells seem to differ from the mesenchymal cells only in form and not in structure, indicating that mesothelium is to be considered not as a tissue differentiated from the mesenchyme, but merely as a change or transformation in form. These observations, together with those of W. C. Clarke, indicate that, in the healing of wounds of the mesothelium lining the peritoneal, pleural, and serous cavities, new mesothelium may arise from the subjacent mesenchyme by the change in form of its cells, and that the repair after abrasions of the mesothelium is not necessarily brought about by a spreading of the adjacent mesothelium over the wound, such as occurs in repair of skin wounds.
Mesothelium
Mesenchyme
Allantois
Ingression
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Connective tissue growth factor (CTGF) plays a major role in pathways that lead to fibrosis, including fibrosis of major organs, fibroproliferative diseases, and scarring. Tissue hypoxia has been reported to induce the expression and secretion of CTGF in various tissues and organs, such as in renal cortical myofibroblasts, in renal interstitial fibroblasts, and in skin. This implicates CTGF as a mechanism of action for tissue damage caused by hypoxia. Studies have shown that cells deficient in hypoxic inducible factor 1 (HIF-1) were not able to produce CTGF mRNA, suggesting a strong association between the two proteins. In this study fibroblast cells were placed under hypoxic conditions for periods of 2, 24, 48, and 72 hours, and the levels of HIF-1, and CTGF were determined by immunocytochemical techniques. The results show a strong positive response to HIF-1 following hypoxia treatment for periods of 24 hours. By 48 and 72 hours HIF-1 levels are reduced and increases in CTGF cellular staining are noticeable. The results of our study also indicate a strong correlation between HIF-1 and CTGF. Our data also shows that once CTGF is induced, HIF-1 levels decline even though the hypoxic conditions are maintained. Determining the relationship between HIF-1 and CTGF may provide a deeper understanding of the pathogenesis of fibroproliferative disease.
Hypoxia
Myofibroblast
CYR61
Pathogenesis
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Objective: To investigate the change of connective tissue factor (CTGF) in adriamycin-induced nephropathy rats, and study the effect of Haikunshenxi on adrimysin-induced nephropathy rats and its possible mechanism.Methods:Half nephrectomize with ADR nephropathy was used. The rats were randomly divided into 6 groups: normal control group, adriamysin-induced nephropathy group, sham operation group, Lotensin treated group and Haikunshenxi low dose and big dose treatment group. Renal tissue were examined by light microscopy at 10 weeks after operation.Immunohistochemistry and in-situ hybridization was applied to measure the expression of CTGF and CTGF mRNA in the nephridial tissue.Results:The expression of CTGF and CTGF mRNA in the nomal and sham operation group is low in the intracytoplasm of Mesangial cells, renaltubular epithelial cells and renal tubular epithelial cells. Compare with sham operation group, the expression of CTGF and CTGF mRNA in the mode group was markedly increased, and the fibrosis of nephridial tissue is obvious. Haikunshenxi could significantly decrease the expression of CTGF and CTGF mRNA (P0.05).Conclusion:Haikunshenxi may suppress the development of fibrosis, at least in part via down-regulating the expression of protein and mRNA of CTGF.
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Abstract The apical ectodermal ridge plays a central role in limb development through its interactions with the underlying mesenchyme. Removal of the AER results in cessation of limb outgrowth and leads to truncation of the limb along the proximo‐distal axis. The many functions attributed to the ridge include maintenance of the progress zone mesenchyme. Here, cells are stimulated to proliferate, are maintained in an undifferentiated state, and are assigned progressively more distal positional values as the limb grows. The AER also functions to maintain the activity of the polarizing region, a region of mesenchyme which is thought to provide the primary signal for patterning along the antero‐posterior axis. We have begun to explore the function of fibroblast growth factor‐4 (FGF‐4) during limb development. FGF‐4, which encodes an efficiently secreted protein, is expressed in the AER. We have previously demonstrated that FGF‐4 protein can stimulate limb mesenchyme proliferation and can induce the expression of a downstream homeobox gene, Evx‐1 (homologue of the Drosophila even‐skipped gene), that is normally regulated by a signal from the AER. To determine to what extent FGF‐4 protein can substitute for the AER to allow normal limb outgrowth, we performed experiments on the developing chick limb in ovo. Remarkably, we find that after AER removal, the FGF‐4 protein can provide all the signals required for virtually normal outgrowth and patterning of the limb. Further studies indicate that proliferation of progress zone cells is not sufficient, and that an additional signal is produced by the posterior mesenchyme in response to FGF‐4 which enables progress zone cells to acquire progressively more distal fates. Thus FGF‐4 maintains progress zone activity through a combination of at least two signals—one that acts directly on progress zone cells to stimulate their proliferation, and one that acts indirectly by maintaining the production of patterning signal(s) by the posterior mesenchyme. We further show that failure of the posterior mesenchyme to produce this signal correlates with failure to maintain polarizing activity. This raises the possibility that the signal produced by the posterior mesenchyme and required for progressive proximo‐distal limb patterning is identical to the polarizing activity. Further experiments demonstrate that retinoic acid, which mimics the activity of the polarizing region, can supply this signal. In conclusion, the finding that a single growth factor can serve as both the direct and indirect signals required to maintain progress zone activity provides a simple mechanism for ensuring that growth and pattern formation are linked in the developing limb. © 1994 Wiley‐Liss, Inc.
Mesenchyme
Limb development
Apical ectodermal ridge
Limb bud
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Abstract Background The fibroblast growth factor (FGF) pathway plays important role in epithelial-mesenchymal interactions during tooth development. However, how the ligands, receptors, and inhibitors of the FGF pathway get involved into the epithelial-mesenchymal interactions are largely unknown in miniature pigs, which can be used as large animal models for similar tooth anatomy and replacement patterns to humans. Results In this study, we investigated the spatiotemporal expression patterns of critical genes encoding FGF ligands, receptors, and inhibitors in the third deciduous molar of the miniature pig at the cap, early bell, and late bell stages. With the methods of fluorescence in situ hybridization and real time RT-PCR, it was revealed that the expression of Fgf3, Fgf4, Fgf7 , and Fgf9 mRNAs were located mainly in the dental epithelium and underlying mesenchyme at the cap stage. The expression levels of Fgf3 and Fgf7 in the mesenchyme were upregulated in the early bell stage and then concentrated in the odontoblasts layer in the late bell stage. In contrast, the expression levels of Fgf4 and Fgf9 in the mesenchyme were downregulated from the cap to bell stage. Gene expression analysis also suggested that Fgfr1 and Fgfr3 were the major receptors regulating dental calcification. Furthermore, the inhibitor-coding genes Sprouty 2 and Sprouty 4 were expressed in the epithelium and mesenchyme in the three stages, indicating that elaborate regulation occurred during dental morphogenesis. Conclusions The spatiotemporal expression pattern of FGF signaling provides the foundation for future studies aiming to fine-tune dental morphogenesis and odontogenesis by controlling the interactions between the dental epithelium and mesenchyme, thereby promoting tooth regeneration in large mammals.
Mesenchyme
FGF9
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Mesenchyme
FGF8
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