scholarly journals Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers

2010 ◽  
Vol 299 (5) ◽  
pp. G1139-G1146 ◽  
Author(s):  
Takako Ae ◽  
Takashi Ohno ◽  
Youichiro Hattori ◽  
Tatsunori Suzuki ◽  
Kanako Hosono ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Growth Factor ◽  
Ulcer Healing ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Gastric Ulcers ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Healing Processes

The importance of prostaglandin E2 in various pathophysiological events emphasizes the necessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no report on the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes of gastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, we tested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement of angiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts. Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulation tissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantly delayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis in ulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and the microvessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such as transforming growth factor-β, basic fibroblast growth factor, and connective tissue growth factor in ulcer granulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The present results suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensable to ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastric ulcers.

Regulation of connective tissue growth factor expression by prostaglandin E2

1999 ◽  
Vol 277 (6) ◽  
pp. L1165-L1171 ◽  
Author(s):  
Dennis A. Ricupero ◽  
David C. Rishikof ◽  
Ping-Ping Kuang ◽  
Christine F. Poliks ◽  
Ronald H. Goldstein
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Collagen Mrna

Transforming growth factor-β (TGF-β) stimulates α1(I) collagen mRNA synthesis in human lung fibroblasts through a mechanism that is partially sensitive to cycloheximide and that may involve synthesis of connective tissue growth factor (CTGF). Northern blot analyses indicate that TGF-β stimulates time- and dose-dependent increases in CTGF mRNA. In TGF-β-stimulated fibroblasts, maximal levels of CTGF mRNA (3.7-fold above baseline) occur at 6 h. The TGF-β-stimulated increase in CTGF mRNA was not blocked by cycloheximide. Nuclear run-on analysis indicates that TGF-β increases the CTGF transcription rate. The TGF-β-stimulated increases in CTGF transcription and steady-state levels of CTGF mRNA are attenuated in prostaglandin E2(PGE2)-treated fibroblasts. PGE2 fails to attenuate luciferase activity induced by TGF-β in fibroblasts transfected with the TGF-β-responsive luciferase reporter construct p3TP-LUX. In amino acid-deprived fibroblasts, PGE2and insulin regulate α1(I) collagen mRNA levels without affecting CTGF mRNA levels. The data suggest that the regulation of α1(I) collagen mRNA levels by TGF-β and PGE2 may function through both CTGF-dependent and CTGF-independent mechanisms.

TGF-β and CTGF have overlapping and distinct fibrogenic effects on human renal cells

2002 ◽  
Vol 283 (4) ◽  
pp. F707-F716 ◽  
Author(s):  
Elizabeth Gore-Hyer ◽  
Daniel Shegogue ◽  
Malgorzata Markiewicz ◽  
Shianlen Lo ◽  
Debra Hazen-Martin ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Growth Factors ◽  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Mrna Levels ◽  
Potent Inducer ◽  
Collagen Promoter

Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are ubiquitously expressed in various forms of tissue fibrosis, including fibrotic diseases of the kidney. To clarify the common and divergent roles of these growth factors in the cells responsible for pathological extracellular matrix (ECM) deposition in renal fibrosis, the effects of TGF-β and CTGF on ECM expression in primary human mesangial (HMCs) and human proximal tubule epithelial cells (HTECs) were studied. Both TGF-β and CTGF significantly induced collagen protein expression with similar potency in HMCs. Additionally, α2(I)-collagen promoter activity and mRNA levels were similarly induced by TGF-β and CTGF in HMCs. However, only TGF-β stimulated collagenous protein synthesis in HTECs. HTEC expression of tenascin-C (TN-C) was increased by TGF-β and CTGF, although TGF-β was the more potent inducer. Thus both growth factors elicit similar profibrogenic effects on ECM production in HMCs, while promoting divergent effects in HTECs. CTGF induction of TN-C, a marker of epithelial-mesenchymal transdifferentiation (EMT), with no significant induction of collagenous protein synthesis in HTECs, may suggest a more predominant role for CTGF in EMT rather than induction of excessive collagen deposition by HTECs during renal fibrosis.

Mechanisms through which bradykinin promotes glomerular injury in diabetes

2005 ◽  
Vol 288 (3) ◽  
pp. F483-F492 ◽  
Author(s):  
Yan Tan ◽  
Bing Wang ◽  
Joo-Seob Keum ◽  
Ayad A. Jaffa
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Collagen I ◽  
Mrna Levels ◽  
Glomerular Injury ◽  
Western Blots ◽  
Protein Levels

In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and TGF-β type II receptor (TGF-βRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-β as well as protein levels of CTGF and TGF-βRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-β mRNA levels expressed relative to β-actin mRNA levels and CTGF and TGF-βRII protein levels were significantly increased in D and D+I rats compared with C rats ( P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-βRII, and collagen I, mesangial cells (MC) were treated with BK (10−8 M) for 24 h and CTGF and TGF-βRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-βRII protein levels was observed in response to BK stimulation ( P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10−8 M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK ( P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 μM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-βRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10−8 M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-βRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-βRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.

scholarly journals Role of transforming growth factor-β1in down-regulating TNF production by alveolar macrophages during asbestos-induced pulmonary fibrosis

1996 ◽  
Vol 5 (1) ◽  
pp. 37-42 ◽  
Author(s):  
Irma Lemaire ◽  
Sophie Ouellet
Keyword(s):  
Growth Factor ◽  
Alveolar Macrophages ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Significant Inhibition ◽  
Prostaglandin E ◽  
Tumour Necrosis Factor Production

Activation of alveolar macrophages (AM) for tumour necrosis factor production is suppressed initially during the inflammatory response to fibrogenic dusts. We investigated the mechanisms involved in TNF suppression, notably the role of other AM-derived mediators including prostaglandin E2(PGE2), transforming growth factor-β1(TGF-β1), and interleukin 6 (IL-6). The action of PGE2and TGF-β1, on AM was different. At physiologically relevant doses (25–300 pg/ml), PGE2did not cause significant inhibition of Hpopolysaccharide (Lps)-induced TNF release by AMin vitrobut stimulated IL-6 (up to six fold), an inhibitor of AM-derived TNT. In contrast, TGF-β1(0.5–50 ng/ml) inhibited both LPS-induced TNT and IL-6 release by 50% but had no effect on PGE2production by AM. To determine the respective contribution of these different inhibitors in TNF suppression, AM from rats exposed to fibrogenic asbestos for weeks were treated with neutralizing antibody against TGF-β1or indomethacin, an inhibitor of PGE2synthesis. Treatment of rat AM with anti-TGF-β1but not indomethacin, abrogated the observed TNT suppression. These results suggest that an autocrine, TGF-β1-dependent mechanism is involved in the down-regulation of TNF production by rat AM from animals with lung fibrosis.

The Role of Transforming Growth Factor ? Formulation on Aspirin-Induced Ulcer Healing and Oxidant Stress in the Gastric Mucosa

Surgery Today ◽  
2004 ◽  
Vol 34 (12) ◽  
pp. 1035-1040 ◽  
Author(s):  
Bilge G�n�l ◽  
K. Gonca Akbulut ◽  
�i?dem �zer ◽  
G�lay Yetkin ◽  
Nevin �elebi
Keyword(s):  
Growth Factor ◽  
Gastric Mucosa ◽  
Ulcer Healing ◽  
Transforming Growth Factor ◽  
Oxidant Stress

scholarly journals Transcryptomic Analysis of Human Brain -Microvascular Endothelial Cell Driven Changes in -Vascular Pericytes

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1784
Author(s):  
Lisa Kurmann ◽  
Michal Okoniewski ◽  
Raghvendra K. Dubey
Keyword(s):  
Growth Factor ◽  
Human Brain ◽  
Cell Survival ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Microvascular Endothelial Cell ◽  
Prostaglandin E ◽  
Pathway Enrichment Analysis ◽  
Strong Impact ◽  
The Impact

Many pathological conditions of the brain are associated with structural abnormalities within the neurovascular system and linked to pericyte (PC) loss and/or dysfunction. Since crosstalk between endothelial cells (ECs) and PCs greatly impacts the function of the blood–brain barrier (BBB), effects of PCs on endothelial integrity and function have been investigated extensively. However, the impact of ECs on the function and activity of PCs remains largely unknown. Hence, using co-cultures of human brain vascular PCs with human cerebral microvascular ECs on opposite sides of porous Transwell inserts which facilitates direct EC–PC contact and improves EC barrier function, we analyzed EC-driven transcriptomic changes in PCs using microarrays and changes in cytokines/chemokines using proteome arrays. Gene expression analysis (GEA) in PCs co-cultured with ECs versus PCs cultured alone showed significant upregulation of 1′334 genes and downregulation of 964 genes. GEA in co-cultured PCs revealed increased expression of five prominent PC markers as well as soluble factors, such as transforming growth factor beta, fibroblast growth factor, angiopoietin 1, brain-derived neurotrophic factor, all of which are involved in EC–PC crosstalk and BBB induction. Pathway enrichment analysis of modulated genes showed a strong impact on many inflammatory and extracellular matrix (ECM) pathways including interferon and interleukin signaling, TGF-β and interleukin-1 regulation of ECM, as well as on the mRNA processing pathway. Interestingly, while co-culture induced the mRNA expression of many chemokines and cytokines, including several CCL- and CXC-motif ligands and interleukins, we observed a decreased expression of the same inflammatory mediators on the protein level. Importantly, in PCs, ECs significantly induced interferon associated proteins (IFIT1, IFI44L, IF127, IFIT3, IFI6, IFI44) with anti-viral actions; downregulated prostaglandin E receptor 2 (prevent COX-2 mediated BBB damage); upregulated fibulin-3 and connective tissue growth factor essential for BBB integrity; and multiple ECMs (collagens and integrins) that inhibit cell migration. Our findings suggest that via direct contact, ECs prime PCs to induce molecules to promote BBB integrity and cell survival during infection and inflammatory insult. Taken together, we provide first evidence that interaction with ECs though porous membranes induces major changes in the transcriptomic and proteomic profile of PCs. ECs influence genes involved in diverse aspects of PC function including PC maturation, cell survival, anti-viral defense, blood flow regulation, immuno-modulation and ECM deposition.

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