Modulation of bcl-2 and p27 in human primitive proliferating hematopoietic progenitors by autocrine TGF-β1 is a cell cycle–independent effect and influences their hematopoietic potential

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3001-3009 ◽  
Author(s):  
Luca Pierelli ◽  
Maria Marone ◽  
Giuseppina Bonanno ◽  
Simona Mozzetti ◽  
Sergio Rutella ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transforming Growth Factor ◽  
Independent Effect ◽  
Hematopoietic Progenitors ◽  
Cycle Number ◽  
Protein Levels ◽  
Bax Protein ◽  
Relevant Effect ◽  
Tgf Β1 ◽  
Rna Levels

Abstract Primitive, proliferating hematopoietic progenitors (defined as cytokine low-responding primitive progenitors; CLRPP), isolated from human CD34+ cells, expressed endoglin (CD105) and produced transforming growth factor-β1 (TGF-β1). Culture of CLRPP in serum-free conditions with anti-TGF-β1 monoclonal antibody produced a substantial decrease in bcl-2 protein/RNA levels and a significant reduction of cloning and long-term culture-initiating cell (LTC-IC) activities. GATA-1 and PU.1 RNA levels were significantly up-regulated in anti-TGF-β1–treated CLRPP, which generated an increased number of cells expressing CD15/CD11b/glycophorin-A. The described effects of TGF-β1 neutralization were observed in the absence of any relevant effect on cell cycle; number of cell divisions; p53, c-myc, and p21 RNA levels; bcl-xL and bax protein levels; and c-myc/p16/p21/p107/Rb cell cycle–related protein levels. A relevant increase in p27 protein levels was observed in anti-TGF-β1–treated CLRPP, suggesting a role for p27 in the regulation of the hematopoietic potential. The present study on human progenitors and previously reported data on TGF-β1 knockout mice suggest that, at the autocrine level, the cell cycle inhibitor TGF-β1 plays an important role in regulating the survival and differentiation of primitive proliferating hematopoietic progenitors by cell cycle–independent mechanisms.

Modulation of bcl-2 and p27 in human primitive proliferating hematopoietic progenitors by autocrine TGF-β1 is a cell cycle–independent effect and influences their hematopoietic potential

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3001-3009 ◽  
Author(s):  
Luca Pierelli ◽  
Maria Marone ◽  
Giuseppina Bonanno ◽  
Simona Mozzetti ◽  
Sergio Rutella ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transforming Growth Factor ◽  
Independent Effect ◽  
Hematopoietic Progenitors ◽  
Cycle Number ◽  
Protein Levels ◽  
Bax Protein ◽  
Relevant Effect ◽  
Tgf Β1 ◽  
Rna Levels

Primitive, proliferating hematopoietic progenitors (defined as cytokine low-responding primitive progenitors; CLRPP), isolated from human CD34+ cells, expressed endoglin (CD105) and produced transforming growth factor-β1 (TGF-β1). Culture of CLRPP in serum-free conditions with anti-TGF-β1 monoclonal antibody produced a substantial decrease in bcl-2 protein/RNA levels and a significant reduction of cloning and long-term culture-initiating cell (LTC-IC) activities. GATA-1 and PU.1 RNA levels were significantly up-regulated in anti-TGF-β1–treated CLRPP, which generated an increased number of cells expressing CD15/CD11b/glycophorin-A. The described effects of TGF-β1 neutralization were observed in the absence of any relevant effect on cell cycle; number of cell divisions; p53, c-myc, and p21 RNA levels; bcl-xL and bax protein levels; and c-myc/p16/p21/p107/Rb cell cycle–related protein levels. A relevant increase in p27 protein levels was observed in anti-TGF-β1–treated CLRPP, suggesting a role for p27 in the regulation of the hematopoietic potential. The present study on human progenitors and previously reported data on TGF-β1 knockout mice suggest that, at the autocrine level, the cell cycle inhibitor TGF-β1 plays an important role in regulating the survival and differentiation of primitive proliferating hematopoietic progenitors by cell cycle–independent mechanisms.

scholarly journals Transforming Growth Factor β1 Receptor II Is Downregulated by E1A in Adenovirus-Infected Cells

2003 ◽  
Vol 77 (17) ◽  
pp. 9324-9336 ◽  
Author(s):  
Vera L. Tarakanova ◽  
William S. M. Wold
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Quiescent Cells ◽  
Growth Inhibitory ◽  
Infected Cells ◽  
Cycle Regulation ◽  
Tgf Β1

ABSTRACT Transforming growth factor β1 (TGF-β1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a “tumor-like” state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-β1 signaling is inhibited. The levels of TGF-β1 receptor II (TβRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TβRII protein was accompanied by a decrease in TβRII mRNA. The decrease in TβRII protein levels in adenovirus-infected cells was greater than the decrease in TβRII mRNA, suggesting that downregulation of the TβRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TβRII protein in infected and uninfected cells were similar. TGF-β1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-β-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TβRII downregulation did not inhibit TGF-β1 signaling. TGF-β1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-β signaling pathway. These results raise the possibility that inhibition of TGF-β signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.

scholarly journals TGF-β1 modifies histone acetylation and acetyl-coenzyme A metabolism in renal myofibroblasts

2019 ◽  
Vol 316 (3) ◽  
pp. F517-F529 ◽  
Author(s):  
Edward R. Smith ◽  
Belinda Wigg ◽  
Stephen G. Holt ◽  
Timothy D. Hewitson
Keyword(s):  
Histone Acetylation ◽  
Transforming Growth Factor ◽  
Aerobic Glycolysis ◽  
Transforming Growth Factor Β1 ◽  
Metabolic Reprogramming ◽  
Acetyl Coa ◽  
Hdac Activity ◽  
Protein Levels ◽  
H3 Acetylation ◽  
Tgf Β1

Histone acetylation is an important modulator of gene expression in fibrosis. This study examined the effect of the pre-eminent fibrogenic cytokine transforming growth factor-β1 (TGF-β1) on histone 3 (H3) acetylation and its regulatory kinetics in renal myofibroblasts. Fibroblasts propagated from rat kidneys after ureteric obstruction were treated with recombinant TGF-β1 or vehicle for 48 h. TGF-β1-induced myofibroblast activation was accompanied by a net decrease in total H3 acetylation, although changes in individual marks were variable. This was paralleled by a generalized reduction in histone acetyltransferases (HAT) and divergent changes in histone deacetylase (HDAC) enzymes at both transcript and protein levels. Globally, this was manifest in a reduction in total HAT activity and increase in HDAC activity. TGF-β1 induced a shift in cellular metabolism from oxidative respiration to aerobic glycolysis, resulting in reduced acetyl-CoA. The reduction in total H3 acetylation could be rescued by providing exogenous citrate or alternative sources of acetyl-CoA without ameliorating changes in HAT/HDAC activity. In conclusion, TGF-β1 produces a metabolic reprogramming in renal fibroblasts, with less H3 acetylation through reduced acetylation, increased deacetylation, and changes in carbon availability. Our results suggest that acetyl-CoA availability predominates over HAT and HDAC activity as a key determinant of H3 acetylation in response to TGF-β1.

scholarly journals Prevention of myocardial fibrosis by N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats

2010 ◽  
Vol 118 (3) ◽  
pp. 211-220 ◽  
Author(s):  
Giovanna Castoldi ◽  
Cira R. T. Di Gioia ◽  
Camila Bombardi ◽  
Carla Perego ◽  
Lucia Perego ◽  
...  
Keyword(s):  
Diastolic Function ◽  
Diabetic Cardiomyopathy ◽  
Transforming Growth Factor ◽  
Systolic Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Doppler Velocity ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Tgf Β1

Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) is a physiological tetrapeptide hydrolysed by ACE (angiotensin-converting enzyme). In experimental models of hypertension, Ac-SDKP has antifibrotic effects in the heart; however, the role of Ac-SDKP in diabetic cardiomyopathy is currently unknown. The aim of the present study was to evaluate the effect of Ac-SDKP on cardiac systolic and diastolic function, and interstitial and perivascular fibrosis in the heart of diabetic rats. Diabetes was induced in 55 Sprague–Dawley rats by streptozotocin injection. Control rats (n=18) underwent only buffer injection. Out of the 55 diabetic rats, 19 were chronically treated with insulin and 13 with the ACEI (ACE inhibitor) ramipril (3 mg·kg−1 of body weight·day−1). At 2 months after the onset of diabetes, Ac-SDKP (1 mg·kg−1 of body weight·day−1) was administered by osmotic minipumps for 8 weeks to eight control rats, 13 diabetic rats, seven diabetic rats treated with ramipril and nine insulin-treated diabetic rats. Diabetic rats had a significant increase in blood glucose levels. Left ventricular interstitial and perivascular fibrosis, and TGF-β1 (transforming growth factor-β1) protein levels were increased in diabetic rats, but not in insulin-treated diabetic rats and ramipril-treated diabetic rats, compared with control rats. Ac-SDKP administration significantly reduced left ventricular interstitial and perivascular fibrosis in diabetic rats and in diabetic rats treated with ramipril. This was accompanied by a significant reduction in active TGF-β1 and phospho-Smad2/3 protein levels in myocardial tissue of diabetic rats. Echocardiography showed that diabetes was associated with increased end-systolic diameters, and depressed global systolic function and diastolic dysfunction, as assessed by transmitral Doppler velocity profile. These changes were completely reversed by insulin or ramipril treatment. Ac-SDKP treatment partially restored diastolic function in diabetic rats. In conclusion, Ac-SDKP administration in diabetic rats reduces left ventricular interstitial and perivascular fibrosis, active TGF-β1 and phospho-Smad2/3 levels, and improves diastolic function. Taken together, these findings suggest that, by inhibiting the TGF-β/Smad pathway, Ac-SDKP protects against the development of diabetic cardiomyopathy.

TAT-mediated PRDX6 protein transduction protects against eye lens epithelial cell death and delays lens opacity

2008 ◽  
Vol 294 (3) ◽  
pp. C842-C855 ◽  
Author(s):  
Eri Kubo ◽  
Nigar Fatma ◽  
Yoshio Akagi ◽  
David R. Beier ◽  
Sanjay P. Singh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lens Epithelial Cell ◽  
Biologically Active ◽  
Lens Epithelial Cells ◽  
Protein Levels ◽  
Endogenous Antioxidant ◽  
Tgf Β1

A diminished level of endogenous antioxidant in cells/tissues is associated with reduced resistance to oxidative stress. Peroxiredoxin 6 (PRDX6), a protective molecule, regulates gene expression/function by controlling reactive oxygen species (ROS) levels. Using PRDX6 protein linked to TAT, the transduction domain from human immunodeficiency virus type 1 TAT protein, we demonstrated that PRDX6 was transduced into lens epithelial cells derived from rat or mouse lenses. The protein was biologically active, negatively regulating apoptosis and delaying progression of cataractogenesis by attenuating deleterious signaling. Lens epithelial cells from cataractous lenses bore elevated levels of ROS and were susceptible to oxidative stress. These cells harbored increased levels of active transforming growth factor (TGF)-β1 and of α-smooth muscle actin and βig-h3, markers for cataractogenesis. Importantly, cataractous lenses showed a 10-fold reduction in PRDX6 expression, whereas TGF-β1 mRNA and protein levels were elevated. The changes were reversed, and cataractogenesis was delayed when PRDX6 was supplied. Results suggest that delivery of PRDX6 can postpone cataractogenesis, and this should be an effective approach to delaying cataracts and other degenerative diseases that are associated with increased ROS.

scholarly journals Antenatal glucocorticoids counteract LPS changes in TGF-β pathway and caveolin-1 in ovine fetal lung

2013 ◽  
Vol 304 (6) ◽  
pp. L438-L444 ◽  
Author(s):  
Jennifer J. P. Collins ◽  
Steffen Kunzmann ◽  
Elke Kuypers ◽  
Matthew W. Kemp ◽  
Christian P. Speer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Western Blot ◽  
Transforming Growth Factor ◽  
Fetal Lung ◽  
Tissue Growth ◽  
Caveolin 1 ◽  
Protein Levels ◽  
Smad2 Phosphorylation ◽  
Ovine Fetal ◽  
Tgf Β1

Inflammation and antenatal glucocorticoids, the latter given to mothers at risk for preterm birth, affect lung development and may contribute to the development of bronchopulmonary dysplasia (BPD). The effects of the combined exposures on inflammation and antenatal glucocorticoids on transforming growth factor (TGF)-β signaling are unknown. TGF-β and its downstream mediators are implicated in the etiology of BPD. Therefore, we asked whether glucocorticoids altered intra-amniotic lipopolysaccharide (LPS) effects on TGF-β expression, its signaling molecule phosphorylated sma and mothers against decapentaplegic homolog 2 (pSmad2), and the downstream mediators connective tissue growth factor (CTGF) and caveolin-1 (Cav-1). Ovine singleton fetuses were randomized to receive either an intra-amniotic injection of LPS and/or maternal betamethasone (BTM) intramuscularly 7 and/or 14 days before delivery at 120 days gestational age (GA; term = 150 days GA). Saline was used for controls. Protein levels of TGF-β1 and -β2 were measured by ELISA. Smad2 phosphorylation was assessed by immunohistochemistry and Western blot. CTGF and Cav-1 mRNA and protein levels were determined by RT-PCR and Western blot. Free TGF-β1 and -β2 and total TGF-β1 levels were unchanged after LPS and/or BTM exposure, although total TGF-β2 increased in animals exposed to BTM 7 days before LPS. pSmad2 immunostaining increased 7 days after LPS exposure although pSmad2 protein expression did not increase. Similarly, CTGF mRNA and protein levels increased 7 days after LPS exposure as Cav-1 mRNA and protein levels decreased. BTM exposure before LPS prevented CTGF induction and Cav-1 downregulation. This study demonstrated that the intrauterine inflammation-induced TGF-β signaling can be inhibited by antenatal glucocorticoids in fetal lungs.

scholarly journals Quercetin Inhibits Cell Survival and Metastatic Ability via the EMT-Mediated Pathway in Oral Squamous Cell Carcinoma

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 757
Author(s):  
So Ra Kim ◽  
Eun Young Lee ◽  
Da Jeong Kim ◽  
Hye Jung Kim ◽  
Hae Ryoun Park
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Transforming Growth Factor ◽  
Hacat Cells ◽  
Mesenchymal Transition ◽  
Anticancer Effects ◽  
Tgf Β1

This study aimed to investigate whether quercetin exerts anticancer effects on oral squamous cell carcinoma (OSCC) cell lines and to elucidate its mechanism of action. These anticancer effects in OSCC cells were assessed using an MTT assay, flow cytometry (to assess the cell cycle), wound-healing assay, invasion assay, Western blot analysis, gelatin zymography, and immunofluorescence. To investigate whether quercetin also inhibits transforming growth factor β1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) in human keratinocyte cells, HaCaT cells were treated with TGF-β1. Overall, our results strongly suggest that quercetin suppressed the viability of OSCC cells by inducing cell cycle arrest at the G2/M phase. However, quercetin did not affect cell viability of human keratinocytes such as HaCaT (immortal keratinocyte) and nHOK (primary normal human oral keratinocyte) cells. Additionally, quercetin suppresses cell migration through EMT and matrix metalloproteinase (MMP) in OSCC cells and decreases TGF-β1-induced EMT in HaCaT cells. In conclusion, this study is the first, to our knowledge, to demonstrate that quercetin can inhibit the survival and metastatic ability of OSCC cells via the EMT-mediated pathway, specifically Slug. Quercetin may thus provide a novel pharmacological approach for the treatment of OSCCs.

scholarly journals Interleukin-13 augments transforming growth factor-β1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts

2005 ◽  
Vol 288 (2) ◽  
pp. C435-C442 ◽  
Author(s):  
XiuXia Zhou ◽  
John B. Trudeau ◽  
Kathryn J. Schoonover ◽  
Jessica I. Lundin ◽  
Steve M. Barnes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Mrna Stabilization ◽  
Protein Levels ◽  
Human Airway ◽  
Tgf Β1

Tissue inhibitor of metalloproteinase (TIMP)-1 is a potent inhibitor of activated matrix metalloproteinases (MMPs) such as gelatinases and collagenases. TIMP-1 is induced by transforming growth factor-β1 (TGF-β1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF-β. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF-β1 (200 pM)-induced expression of TIMP-1 mRNA and protein in primary human airway fibroblasts obtained from 57 human subjects. IL-13 alone had no effect on TIMP-1 mRNA or protein expression. However, IL-13 synergistically augmented TGF-β1-induced TIMP-1 mRNA and protein expression ( P < 0.001 vs. TGF-β1 alone). The upregulation of TIMP-1 by the combination of TGF-β1 and IL-13 involved increased transcription, with little effect on mRNA stabilization. Initial exploration of the pathways leading to the synergy determined that activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway by IL-13 may have a negative effect on TIMP-1 production. The specific PI3K inhibitor LY-294002 in the presence of TGF-β1, IL-13, or the combination of the two caused significant increases in TIMP-1 mRNA expression, while LY-294002 increased TIMP-1 protein levels in the presence of IL-13 alone. These results suggest that IL-13 augments TGF-β1-induced profibrotic responses at both the mRNA and protein levels. Although IL-13 induced activation of PI3K-Akt, the activation did not contribute to the synergy observed with TGF-β1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.

Transforming growth factor β1 mediates cell-cycle arrest of primitive hematopoietic cells independent of p21Cip1/Waf1or p27Kip1

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3643-3649 ◽  
Author(s):  
Tao Cheng ◽  
Hongmei Shen ◽  
Neil Rodrigues ◽  
Sebastian Stier ◽  
David T. Scadden
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Hematopoietic Cells ◽  
Transforming Growth Factor Β1 ◽  
Primitive Cell ◽  
Hematopoietic Stem ◽  
Tgf Β1

Abstract The regulation of stem cell proliferation is a poorly understood process balancing rapid, massive blood cell production in times of stress with maintenance of a multipotent stem cell pool over decades of life. Transforming growth factor β1 (TGF-β1) has pleiotropic effects on hematopoietic cells, including the inhibition of primitive cell proliferation. It was recently demonstrated that the cyclin-dependent kinase inhibitors, p21Cip1/Waf1 (p21) and p27Kip1 (p27), can inhibit the proliferation of hematopoietic stem cells and progenitor cells, respectively. The relation of TGF-β1 stimulation to p21 and p27 was examined using a fine-mapping approach to gene expression in individual cells. Abundant TGF-β1 expression and p21 expression were documented in quiescent, cytokine-resistant hematopoietic stem cells and in terminally differentiated mature blood cells, but not in proliferating progenitor cell populations. TGF-β1 receptor (TβR II) was expressed ubiquitously without apparent modulation. Cell- cycle–synchronized 32D cells exposed to TGF-β1 demonstrated a marked antiproliferative effect of TGF-β1, yet neither the level of p21 mRNA nor the protein level of either p21 or p27 was altered. To corroborate these observations in primary cells, bone marrow mononuclear cells derived from mice engineered to be deficient in p21 or p27 were assessed. Progenitor and primitive cell function was inhibited by TGF-β1 equivalently in −/− and +/+ littermate controls. These data indicate that TGF-β1 exerts its inhibition on cell cycling independent of p21 and p27 in hematopoietic cells. TGF-β1 and p21 or p27 participate in independent pathways of stem cell regulation, suggesting that targeting each may provide complementary strategies for enhancing stem or progenitor cell expansion and gene transduction.

Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice

2009 ◽  
Vol 297 (6) ◽  
pp. F1510-F1517 ◽  
Author(s):  
Kei Kurata ◽  
Shoichi Maruyama ◽  
Sawako Kato ◽  
Waichi Sato ◽  
Jun-ichiro Yamamoto ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Basement Membranes ◽  
Tissue Type ◽  
Vascular Density ◽  
Peritoneal Fibrosis ◽  
Plasmin Activity ◽  
Protein Levels ◽  
Tgf Β1

Peritoneal fibrosis (PF) is an important complication of peritoneal dialysis therapy. The present study was performed to examine the mechanisms of PF in view of the plasminogen activator (PA)/plasmin/matrix metalloproteinase (MMP) cascade. PF was induced in tissue-type PA (tPA) deficient mice and wild-type mice by intraperitoneal injection of chlorhexidine gluconate. Mice were killed on day 21, and tissue samples were taken. Histopathological studies were performed. Plasmin activity, gelatinases activity, and the levels of tPA, transforming growth factor-β1 (TGF-β1), and MMP-2 mRNA were determined. Protein levels of MMP-3, tissue inhibitor of metalloproteinases (TIMP)-1, -2, and -3, phospho-Smad3, membrane-type 1 (MT1)-MMP, and MT3-MMP were also studied. On day 21, tPA +/+ mice showed severe PF, whereas tPA −/− mice showed milder change. Submesothelial basement membranes were dissolved in tPA +/+ mice while they were relatively preserved in tPA −/− mice. The levels of macrophage infiltration, staining for α-smooth muscle actin (α-SMA) and collagen type III, and vascular density were all significantly lower in tPA −/− mice than in tPA +/+ mice. The levels of plasmin activity, pro- and active MMP-2, mRNA expression of tPA and TGF-β1, and phospho-Smad3 protein were also lower in tPA −/− mice. No difference was observed between the two groups concerning the protein levels of MMP-3, TIMP-1, TIMP-2, TIMP-3, MT1-MMP, or MT3-MMP. These results indicate that the presence of tPA enhances inflammation, angiogenesis, and fibrogenesis in the peritoneum of the PF model mice. Activation of the PA/plasmin/MMP cascade may play a pivotal role in the pathogenesis of PF.

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