Systemic sclerosis (SSc) is a connective tissue disorder characterised by the development of skin fibrosis. Our current understanding of the disease pathogenesis is incomplete and the study of SSc is hindered, at least partially, by a lack of animal models that fully replicate the complex state of human disease. Murine model of bleomycin-induced dermal fibrosis encapsulates important events that take place early in the disease course. To characterise the optimum in vivo parameters required for the successful induction of dermal fibrosis we subjected three commonly used mouse strains to repeated subcutaneous bleomycin injections. We aimed to identify the effects of genetic background and gender on the severity of skin fibrosis. We used male and female Balb/C, C57BL/6, and DBA/2 strains and assessed their susceptibility to bleomycin-induced fibrosis by measuring dermal thickness, hydroxyproline/collagen content and number of resident myofibroblasts, all of which are important indicators of the severity of

Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose

Fibroproliferative disorders such as idiopathic pulmonary fibrosis and systemic sclerosis have no effective therapies and result in significant morbidity and mortality due to progressive organ fibrosis. We examined the effect of peptides derived from endostatin on existing fibrosis and fibrosis triggered by two potent mediators, transforming growth factor-β (TGF-β) and bleomycin, in human and mouse tissues in vitro, ex vivo, and in vivo. We identified one peptide, E4, with potent antifibrotic activity. E4 prevented TGF-β-induced dermal fibrosis in vivo in a mouse model, ex vivo in human skin, and in bleomycin-induced dermal and pulmonary fibrosis in vivo, demonstrating that E4 exerts potent antifibrotic effects. In addition, E4 significantly reduced existing fibrosis in these preclinical models. E4 amelioration of fibrosis was accompanied by reduced cell apoptosis and lower levels of lysyl oxidase, an enzyme that cross-links collagen, and Egr-1 (early growth response gene-1), a transcription ...

Interstitial fibrosis can be an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). suppressed the immunoreactivity of mTOR signaling, which decreased the inflammatory responses and ECM accumulation in the obstructed kidneys. Isolated macrophages from rapamycin-treated obstructed kidneys presented less inflammatory activity than vehicle groups. In vitro study confirmed that rapamycin significantly inhibited the fibrogenic activation of cultured fibroblasts (NIH3T3 cells), which was induced by the stimulation of TGF-1. Further experiment revealed that rapamycin did not directly inhibit the fibrogenesis of HK2 cells with aristolochic acid treatment. Our findings clarified that rapamycin can ameliorate kidney fibrosis by blocking the mTOR signaling in interstitial macrophages and myofibroblasts. Introduction Tubulointerstitial fibrosis is the final common pathway of a wide variety of chronic progressive kidney diseases. Intense studies have focused on the molecular and ...

TY - JOUR. T1 - Associations of electrocardiographic P-wave characteristics with left atrial function, and diffuse left ventricular fibrosis defined by cardiac magnetic resonance. T2 - The PRIMERI study. AU - Win, Theingi Tiffany. AU - Venkatesh, Bharath Ambale. AU - Volpe, Gustavo J.. AU - Mewton, Nathan. AU - Rizzi, Patricia. AU - Sharma, Ravi K.. AU - Strauss, David G.. AU - Lima, Joao A.. AU - Tereshchenko, Larisa G.. PY - 2015/1/1. Y1 - 2015/1/1. N2 - BACKGROUND: Abnormal P-terminal force in lead V1 (PTFV1) is associated with an increased risk of heart failure, stroke, atrial fibrillation, and death. OBJECTIVE: Our goal was to explore associations of left ventricular (LV) diffuse fibrosis with left atrial (LA) function and electrocardiographic (ECG) measures of LA electrical activity. METHODS: Patients without atrial fibrillation (n = 91; mean age 59.5 years; 61.5% men; 65.9% white) with structural heart disease (spatial QRS-T angle ≥105° and/or Selvester QRS score ≥5 on ECG) but LV ...

Background: Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. Methods: LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. Results: On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P , 0.001), which remained significant on ...

Introduction: Late-gadolinium enhanced cardiac MRI (LGE-MRI) is used to quantify atrial tissue fibrosis. We studied the impact of atrial fibrosis in atrial fibrillation (AF) on ventricular tissue. We hypothesized that atrial fibrosis is associated with ventricular involvement manifested by QRS widening and conduction system disease (CSD).. Methods: 427 patients with AF were included. ECGs were analyzed for QRS duration and the presence of CSD including left bundle branch block (LBBB), right bundle branch block (RBBB) and left anterior fascicular block (LAFB). LGE-MRI quantification of atrial tissue fibrosis was performed. Patients were staged as follows: Utah stage I (atrial fibrosis 35%). Patient demographics and clinical data were included in the analysis.. Results: The average QRS duration in Utah stage I was 92±11 ms, 95±18 ms in stage II, 96±19 ms in stage III and 100±26 ms in stage IV (p,0.05). 42 patients (9.83%) had RBBB, 17 (4.0%) had LAFB and 10 (2.3%) had LBBB. CSD was found in 3 ...

Renal fibrosis is characterized by activation and proliferation of fibroblasts, which continually produce and deposit ECM proteins, leading to progressive fibrosis. Herein we demonstrate that GSK3β is expressed in myofibroblasts, and GSK3β expression and activity are increased in mouse kidneys following I/R and in cultured fibroblasts following TGF-β1 treatment. Pharmacological inhibition of GSK3 using TDZD significantly reduced pro-inflammatory and pro-fibrotic cytokines, macrophage infiltration and ECM deposition, thereby reducing fibrosis. GSK3 inhibition reduced the myofibroblast population in vivo and fibroblast-to-myofibroblast differentiation in vitro by a TGF-β-SMAD signaling-dependent mechanism. Thus, GSK3β plays a pro-fibrotic role in the kidney following I/R, and its inhibition, even after the injury has occurred, could prevent the future development of fibrosis.. GSK3β is expressed in proximal tubules (Nørregaard et al., 2015), and increased GSK3β has been detected in renal ...

In the pathogenesis of renal fibrosis, oxidative stress (OS) enhances the production of reactive oxygen species (ROS) leading to sustained cell growth, inflammation, excessive tissue remodelling and accumulation, which results in the development and acceleration of renal damage. In our previous work (128) we established protein DJ-1 (PARK7) as an important ROS scavenger and key player in renal cell response to OS. In the present study we investigated the impact of profibrogenic agonists on DJ-1 and shed light on the role of this protein in renal fibrosis. Treatment of renal fibroblasts and epithelial cells with the profibrogenic agonist ANG II or PDGF resulted in a significant up-regulation of DJ-1 expression parallel to an increase in the expression of fibrosis markers. Monitoring of DJ-1 expression in kidney extract and tissue sections from renal fibrosis mice model (Col4a3-deficient) revealed a disease grad dependent regulation of the protein. Overexpression of DJ-1 prompted cell resistance ...

A total of 32 patients (36.4%) had hypertension, 21 (23.9%) with hyperlipidemia, 9 (10.2%) with diabetes, 6 (6.8%) patients had with a history of tobacco abuse and 10 (11.4%) with coronary artery disease. A total of 38 (43.2%) patients were on statin, 25 (28.4%) were on angiotensin converting enzyme inhibitor, 36 (40.9%) were on a beta-°©-blocker, 31 (35.2%) were on anticoagulant, and 13 (14.8%) were on antiarrhythmic medication. Subsequent follow-°©-up MRIs were performe on 32 (36%) patients that exhibited progression of atrial fibrosis.. Using univariate logistic regression models we were not able to identify significant predictors of fibrosis progression. The majority of patients (64%) did not reveal any significant changes from the initial quality and quantity of atrial fibrosis at 1 year MRI follow-up. ...

Perhaps our most noteworthy finding is the demonstration of myocardial fibrosis after long-term, intensive exercise training. RV fibrosis was documented by collagen quantification in histological sections and analysis of hydroxyproline content. These observations were functionally paralleled by the development of RV diastolic dysfunction, with impaired relaxation potentially related to fibrotic infiltration. Moreover, we noted an increase in mRNA and protein expression of a series of fibrotic markers in the RV and in both atria. TGF-β1 expression was increased in the RA, LA, and RV after 16 weeks of intensive exercise. TGF-β1 is a potent stimulator of collagen-producing cardiac myofibroblasts22 and leads to fibrosis development. Experimental studies have reported that both genetic ablation of TGF-β1 in mice23 and treatment with anti-TGF-β1 antibodies24 inhibit fibrosis development, indicating that TGF-β1 plays a major role in collagen turnover. We also noted enhanced expression of other ...

The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA) induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD) rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously); DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered); DOCA and Aliskiren (ALI) treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively). Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF) and perivascular collagen volume area (PVCA) were calculated. Radioimmunoassay was carried out to measure the renin activity (RA) and content of angiotensin II (Ang II) in the plasma and ventricle. Western blot assay was done to detect the ...

The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA) induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD) rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously); DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered); DOCA and Aliskiren (ALI) treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively). Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF) and perivascular collagen volume area (PVCA) were calculated. Radioimmunoassay was carried out to measure the renin activity (RA) and content of angiotensin II (Ang II) in the plasma and ventricle. Western blot assay was done to detect the ...

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-β1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in ...

Cysteine-rich protein 61 (Cyr61) is a secreted matrix-associated protein that regulates a broad spectrum of biological and cellular activities. This study aimed to investigate the role of Cyr61 in progressive kidney fibrosis induced by unilateral ureteral obstruction (UUO) surgery in mice. The expression of Cyr61 transcripts and proteins in the obstructed kidneys were increased from day 1 and remained high until day 10 after surgery. Immunohistochemistry indicated that Cyr61 was expressed mainly in renal tubular epithelial cells. The upregulated Cyr61 in UUO kidneys was reduced in mice treated with pan-transforming growth factor-β (TGF-β) antibody. The role of TGF-β in tubular Cyr61 upregulation after obstructive kidney injury was further supported by experiments showing that TGF-β1 stimulated Cyr61 expression in cultured tubular epithelial cells. Notably, the upregulation of Cyr61 in UUO kidneys was followed by a marked increase in monocyte chemoattractant protein 1 (MCP-1) ...

Finding a gene for familial cardiac fibrosis (NHS grant 2000.130) Summary of results. A large multi-generation family with an autosomal dominantly inherited form of cardiac fibrosis with a highly malignant clinical outcome is presented and used to identify the gene causing this disease. We consider it a hereditary form of cardiac fibrosis since it was shown that the myocardial fibrosis in this family preceded the clinical and echocardiographic signs.. Twenty-four individuals from this family were clinically evaluated and 18 of them were used for a genome wide linkage analysis giving the highest LOD score (2.6) in the region of the lamin AC (LMNA) gene. Mutation analyses of this candidate gene failed to show a point mutation. Subsequent Southern blot and multiplex ligation-dependent probe amplification analyses, however, revealed a deletion of the start-codon containing exon. The up- and downstream flanking exons proved not to be deleted.. Furthermore, we demonstrate in-vitro that the deletion ...

The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, ...

2015 The Authors. Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor-β1 (TGF-β1) stimulates the production of NADPH oxidase 4 (NOX4)-dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR-9-5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF-β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR-9-5p abrogates TGF-β1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in ...

The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury. Leemans, Jaklien C.; Butter, Loes M.; Pulskens, Wilco P. C.; Teske, Gwendoline J. D.; Claessen, Nike; van der Poll, Tom; Florquin, Sandrine // PLoS ONE;2009, Vol. 4 Issue 5, p1 Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals.... ...

The biology of heart failure is complex and diverse (2), posing challenges for developing efficacious therapies. All but one recent phase III heart failure trial failed to reduce mortality (3). Unlike oncology, we do not split heart failure into subtypes on the basis of disease pathways (4). We need a more targeted approach, not only for drug development, but also for drug response monitoring. Myocardial fibrosis is an attractive biomarker-fibrosis is already an established marker in the liver, kidneys, and lung-and likely a causal disease pathway mediating outcomes. Cardiac fibrosis can be measured on myocardial biopsy and tracks disease severity and outcome (5,6). But biopsy is invasive and impractical for routine clinical diagnosis and monitoring (7). Many of our current measurements are partial surrogates for fibrosis (e.g., imaging for cardiac remodeling, systolic and diastolic function), but more are needed, particularly circulating blood biomarkers. Cardiology quantifies only 2 myocardial ...

TY - JOUR. T1 - A DDX5 S480A polymorphism is associated with increased transcription of fibrogenic genes in hepatic stellate cells. AU - Guo, Jinsheng. AU - Hong, Feng. AU - Loke, Johnny. AU - Yea, Steven. AU - Lim, Chooi Ling. AU - Lee, Ursula. AU - Mann, Derek A.. AU - Walsh, Martin J.. AU - Sninsky, John J.. AU - Friedman, Scott L.. PY - 2010/2/19. Y1 - 2010/2/19. N2 - We recently identified a missense single nucleotide polymorphism (SNP) in DDX5 (rs1140409, p.S480A) that enhances the risk of developing cirrhosis. DDX5 is an ATP-dependent RNA helicase and transcriptional modulator. We hypothesized that the activity of DDX5 in regulating fibrogenic gene transcription in hepatic stellate cells (HSCs) is altered by the S480A SNP. To test this, we employed two approaches: 1) transient overexpression of DDX5 cDNA or siRNA knockdown of endogenous DDX5, with replacement by either DDX5 wild type (WT) or SNP cDNA, or 2) stable expression of exogenous DDX5 WT and SNP in HSC lines. WT DDX5 mRNA in HSCs ...

Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. Even though these pathological manifestations constitute a major public health problem, diagnostic tests, as well as therapeutic options, are currently limited. Members of the dickkopf (DKK) family, DKK1 and -2, have been associated with inhibition of Wnt signaling and organ fibrosis. Here, we identify DKK3 as a stress-induced, tubular epithelia-derived, secreted glycoprotein that mediates kidney fibrosis. Genetic as well as antibody-mediated abrogation of DKK3 led to reduced tubular atrophy and decreased interstitial matrix accumulation in two mouse models of renal fibrosis. This was facilitated by an amplified, antifibrogenic, inflammatory T cell response and diminished canonical Wnt/β-catenin signaling in stressed tubular epithelial cells. Moreover, in humans, urinary DKK3 levels specifically correlated with the ...

Results Females in all three groups had significantly increased septal myocardial ECV compared with males (0.29±0.03 vs 0.25±0.03, p,0.01). Septal myocardial ECV was higher in ALMS than hypertensive and controls (0.28±0.02 vs 0.25±0.03 vs 0.24±0.03, p,0.05). Three male older ALMS patients (mean 43±5 years vs 27±10 years) without a history of infantile CM had patchy diffuse LE in non-coronary artery territories with an increased ECV compared to remote normal myocardium (ECV 0.41±0.08 vs 0.27±0.03, p,0.05). MAPSE was reduced in patients with ALMS and hypertension compared to controls (13±2 cm/s vs 12±3 cm/s vs 17±2 cm/s, p,0.01. There were no differences in LV ejection fraction, LV mass or LA volumes. Septal myocardial ECV was negatively correlated with a MAPSE in patients with ALMS (r=−0.64, p,0.05). NT-BNP was not correlated with septal ECV but was increased in patients with LGE (median 178 pmol/l vs 44 pmol/l).. ...

The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, ...

The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, ...

Results: ACC Ser79 phosphorylation was reduced in folate-treated tubular epithelial cells (p,0.01) and WT mice with FAN (p,0.05). Mutation of these sites in ACC1/2 KI mice with FAN or UUO caused lipid accumulation (Oil Red O p,0.01), increased triglyceride (p,0.01), increased collagen (PicroSirius red p,0.001; Massons Trichrome p,0.01; qRT-PCR p,0.01) and increased α-SMA (Western blot p,0.05; qRT-PCR p,0.01). Metformin administration was associated with reduced fibrosis (PicroSirius red p,0.01) and lipid accumulation (Oil Red O p,0.05) in WT mice, but not in ACC1/2KI mice. To determine the role of glycolysis, UUO was induced in PFKFB2KI mice. WT mice with UUO had reduced PFKFB2 Ser483 phosphorylation (p,0.01). PFKFB2KI UUO mice had increased collagen (Picrosirius red p,0.001), increased fibronectin (Western blot p,0.05; qRT-PCR p,0.05) increased α-SMA (Western blot, p,0.05) and glycogen accumulation (PAS, p,0.05 ...

Abstract. Tubulointerstitial renal fibrosis, characterized as a progressive detrimental connective tissue deposition on the kidney parenchyma, appears to be a harmful process leading inevitably to renal function deterioration, independently of the primary renal disease which causes the original kidney injury. Epithelial to Mesenchymal Transition (EMT) of tubular epithelial cells which are transformed to mesenchymal fibroblasts migrating to adjacent interstitial parenchyma constitutes the principal mechanism of renal fibrosis along with local and circulating cells. Proteinuria as well as hypoxia is included among the main mechanisms of EMT stimulation. TGFβ-1 through the SMAD pathway is considered as the main modulator regulating the EMT molecular mechanism, probably in cooperation with hypoxia inducible factors. Hepatocyte Growth Factor (HGF) and Bone Morphogenetic Factor-7 (BMF-7) are inhibitory to EMT molecules which could prevent in experimental and clinical level the catastrophic process of ...

A major pathophysiological component of cardiac remodeling during heart failure (HF), cardiac fibrosis has become a target for therapeutic intervention. Additionally, compelling evidence indicates a key role of cardiac fibrosis in myocardial malfunctioning during aging. Cardiac fibrosis is a complex phenomenon resulting from aberrant activation of various cell types and signaling pathways as a consequence of injury or damage to tissue. It develops over a time course that also depends upon the type of noxa activation of tissue-specific repair programs, resulting in the subsequent activation of proliferation and migration of fibroblasts from different myocardial locations to the injury site, where they synthesize extracellular matrix (ECM) (1,2).. Tissue repair through the synthesis of new ECM by fibroblasts is beneficial, particularly after myocardial infarction. However, prolonged activation of this process results in excess scar tissue formation, increased ECM deposition, and therefore, bad ...

Scientists at the University of Birmingham, UK, have shown that a novel low molecular weight dextran-sulphate, ILB could play a key role in treating open angle glaucoma (OAG), a neurodegenerative disease that affects over 70 million people worldwide and causes irreversible blindness.

Most pro-fibrogenic polypeptides are produced by infiltrating immune, inflammatory, mesenchymal and tissue-specific cells, thereby facilitating paracrine pro-fibrogenic effects that perpetuate inflammation-driven fibrosis (see below) (Figure 2, Figure 3) [12]. One of the most potent pro-fibrogenic cytokines in vivo is TGFβ. Three TGFβ isoforms have been described to date (TGFβ1, TGFβ2 and TGFβ3), all of which are initially generated as latent precursors [70]. When active TGFβ is liberated, it binds to a heterodimeric receptor complex consisting of one TGFβ type I receptor molecule, termed activin-linked kinase (ALK)5, and one TGFβ type II receptor. In the canonical TGFβ pathway in normal fibroblasts, ligand binding leads ALK5 to phosphorylate Smad2 and 3, which in turn bind to Smad4 to form a complex that is translocated to the nucleus, which activates transcription [71]. However, TGFβ has also been shown to signal via several additional pathways, including p38 mitogen-activated ...

Results TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation. ...

http://www.ncbi.nlm.nih.gov/pubmed/24819852 Eur Heart J Cardiovasc Imaging. 2014 May 12. [Epub ahead of print] A comprehensive evaluation of myocardial fibrosis in hypertrophic cardiomyopathy with cardiac magneticresonance imaging: linking genotype with fibrotic phenotype. Ellims AH1, Iles LM, Ling LH, Chong B, Macciocca I, Slavin GS, Hare JL, Kaye DM, Marasco SF, McLean CA, James PA, du Sart…

The European Union commits funds to the FIBRO-TARGETS (Targeting cardiac fibrosis for heart failure treatment) research consortium, to be coordinated by Inserm over a four-year period. The objective of the project is to determine the underliying mechanisms in myocardial interstitial fibrosis contributing to the development of heart failure.

Dr Peter Millett chats about arthrofibrosis, and why patients with established arthrofibrosis need to seek out a surgeon who is expert in this potentially devastating complication.

TY - JOUR. T1 - Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis. AU - Bigaeva, Emilia. AU - Puerta Cavanzo, Nataly. AU - Stribos, Elisabeth G D. AU - de Jong, Amos J. AU - Biel, Carin. AU - Mutsaers, Henricus A M. AU - Jensen, Michael S. AU - Nørregaard, Rikke. AU - Leliveld, Anna M. AU - de Jong, Igle J. AU - Hillebrands, Jan-Luuk. AU - van Goor, Harry. AU - Boersema, Miriam. AU - Bank, Ruud A. AU - Olinga, Peter. PY - 2020/5/18. Y1 - 2020/5/18. N2 - Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGF beta or PDGF pathway inhibitors ...

Cystic fibrosis is an inherited chronic disease that affects the lungs and digestive system. A defective gene and its protein product cause the body to produce unusually thick, sticky mucus.. Cystic fibrosis Symptoms:. Clogs the lungs and leads to life-threatening lung infections;. Obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.. Now researchers are discovering that cystic fibrosis can be found among adults also and it is more complicated than what the doctors earlier assumed.. In fact many people have this disease since childhood but it is not identified till they grows adults .Many patients are identified as having a mild version of the disease but in its classic form, can quickly attack lungs.. In the 1950s, few children with cystic fibrosis lived to attend elementary school. Today, advances in research and medical treatments have further enhanced and extended life for children and adults with CF. Many people with the disease can now expect ...

In this work, we present an automatic method for liver segmentation and fibrosis classification in liver computed-tomography (CT) portal phase scans. The input is a full abdomen CT scan with an unknown number of slices, and the output is a liver volume segmentation mask and a fibrosis grade. A multi-stage analysis scheme is applied to each scan, including: volume segmentation, texture features extraction and SVM based classification. Data contains portal phase CT examinations from 80 patients, taken with different scanners. Each examination has a matching Fibroscan grade. The dataset was subdivided into two groups: first group contains healthy cases and mild fibrosis, second group contains moderate fibrosis, severe fibrosis and cirrhosis. Using our automated algorithm, we achieved an average dice index of 0.93 ± 0.05 for segmentation and a sensitivity of 0.92 and specificity of 0.81for classification. To the best of our knowledge, this is a first end to end automatic framework for liver ...

The relentless progression of renal disease is closely linked to the process of fibrosis, which is triggered by initial or ongoing injury. Although it is still a point of debate, there is literature to support a mechanistic rather than merely an associative role of fibrosis in progression of kidney disease [40]. This systematic review is a comprehensive evaluation of renal biomarkers that can be used in the detection of fibrosis as well as in the prediction of progression of renal disease. However, the development of a clinically useful biomarker is a sequential process that usually requires five phases; phase 1 identifies promising directions in preclinical studies, phase 2 is clinical assay validation and detection of established disease, phase 3 is biomarker prediction of clinical disease in longitudinal studies, phase 4 is prospective screening and finally phase 5 is impact of screening on disease burden [41]. This systematic review aimed to identify fibrosis biomarkers that achieved phase 2 ...

Ophthotech Corporation (New York, NY) has initiated the first of several planned expansion trials to investigate the potential role of Fovista (anti-platelet derived growth factor, anti-PDGF) combination therapy in reducing subretinal fibrosis, addressing suboptimal treatment response, and reducing treatment burden in wet-AMD patients receiving anti-VEGF monotherapy. The first expansion trial is a phase 2a open-label study investigating the potential role of anti-PDGF therapy in combination with anti-VEGF therapy in reducing subretinal fibrosis in wet-AMD patients.. The anti-PDGF phase 3 program consists of 3 clinical trials to evaluate the safety and efficacy of anti-PDGF for use in combination with anti-VEGF agents for the treatment of wet AMD. Ophthotech expects to enroll up to 1866 patients in the 3 trials in more than 225 centers worldwide and to have initial, topline data from the phase 3 clinical trial available in 2016.. Updated August 5, 2014. ...

The liver organ lymphocyte population is enriched with organic killer (NK) cells, which play a key part in sponsor protection against viral infection and tumor transformation. IL-4, IL-13, hedgehog ligands, and osteopontin; nevertheless, NKT cells may also attenuate liver organ fibrosis under particular circumstances by eliminating HSCs and by generating IFN-. Finally, the potential for NKT and NK cells to be used as therapeutic targets for anti-fibrotic therapy is talked about. proof for the contact between NK cells and early turned on HSCs. (that NK cells eliminate early turned on, but not really quiescent or turned on completely, HSCs. Initial, the amount of early turned on desmin positive HSCs with an oval form was considerably reduced in DDC-fed MLN9708 rodents after administration of the NK cell activator poly I:C (Radaeva and Gao, MLN9708 unpublished data). Second, immunohistochemistry MLN9708 studies present that early turned on HSCs and NK cells possess very similar distributions ...

Fibrosis is the excessive accumulation of extracellular matrix that often occurs as a wound healing response to repeated or chronic tissue injury, and may lead to the disruption of organ architecture and loss of function. Although fibrosis was previously thought to be irreversible, recent evidence indicates that certain circumstances permit the resolution of fibrosis when the underlying causes of injury are eradicated. The mechanism of fibrosis resolution encompasses degradation of the fibrotic extracellular matrix as well as elimination of fibrogenic myofibroblasts through their adaptation of various cell fates, including apoptosis, senescence, dedifferentiation, and reprogramming. In this Review, we discuss the present knowledge and gaps in our understanding of how matrix degradation is regulated and how myofibroblast cell fates can be manipulated, areas that may identify potential therapeutic approaches for fibrosis.. ...

14. Chen, C.A., Tseng, W.Y.I., Wang, J.K., Chen, S.Y., Ni, Y.H., Huang, K.C., Ho, Y.L., Chang, C.I., Chiu, I.S., Su, M.Y.M., Yu, H.Y., Lin, M.T., Lu, C.W., Wu, M.H.*. 2013. Circulating biomarkers of collagen type I metabolism mark the right ventricular fibrosis and adverse markers of clinical outcome in adults with repaired tetralogy of Fallot. International Journal of Cardiology; 167(6):2963-8. ...

A serious complication of radiotherapy in the treatment of cancer patients is the late onset of fibrosis in normal tissues. Transforming growth factor beta (TGF-beta) is emerging as a key mediator of the fibrotic process through its effects on stimulation of fibroblast proliferation, migration and extracellular matrix (ECM) synthesis. The fact that radiation-induced vascular injury tends to precede the development of fibrosis has led to the suggestion that vascular damage is crucial in its pathogenesis. CD105, the specific type III vascular receptor for TGF-beta1 and -beta3, modulates cell proliferation and ECM production in response to TGF-beta in vitro. In this study, we have quantified the levels of TGF-beta1 and soluble CD105-TGF-beta1 complex in 91 pre-radiotherapy plasma samples from early-stage (T1 or T2) breast cancer patients utilising an enhanced chemiluminescence ELISA system. During the follow-up period, 24 patients had developed moderate and one severe fibrosis of the breast. The ...

Interstitial cells in the scars of human myocardial infarctions of different postinfarction times (6 hours to 17 years old) were characterized by antibodies to alpha-smooth muscle actin (ASMA), vimentin, and desmin. Basal lamina deposition was studied with antibodies to the basal lamina protein type …

Cystic fibrosis is a progressive genetic disease wherein the body produces thick and sticky mucus that clogs the lungs and obstructs the pancreas. Cystic fibrosis can be life-threatening, and patients who suffer from it tend to have a short life span. Cystic fibrosis affects some 30,000 people in the United States, and around 1,000 new cases […]

What is cystic fibrosis? Cystic fibrosis is a genetic disease that causes mucus in the body to become thick and sticky. This glue-like mucus builds up and causes problems in many of the bodys organs, especially the lungs and the pancreas. People who have cystic fibrosis can have serious breathing problems and lung...

What is cystic fibrosis? Cystic fibrosis is a genetic disease that causes mucus in the body to become thick and sticky. This glue-like mucus builds up and causes problems in many of the bodys organs, especially the lungs and the pancreas. People who have cystic fibrosis can have serious breathing problems and lung...

This topic contains 7 study abstracts on Renal tubulointerstitial fibrosis indicating that the following substances may be helpful: Angelica, Astragalus, and Mangiferin

This is an open label, single center study to determine the efficacy and safety of ambrisentan and antifibrotic agent combination in systemic sclerosis. Up to twenty patients will be recruited within the next year who have early diffuse systemic sclerosis and are presently receiving treatment with any of the following antifibrotic agents - cellcept, colchicine, azathioprine, D-penicillamine, methotrexate or cyclophosphamide. Ambrisentan will be added to the present agent and then followed for 12 months.. Patients, male or female, , 18 years with a clinical diagnosis of systemic sclerosis fulfilling the criteria of the American College of Rheumatology (formerly the American Rheumatism Association) classification criteria for systemic sclerosis (24), and diffuse cutaneous involvement based on the criteria of LeRoy et al. A thorough baseline evaluation will determine the extent and severity of systemic sclerosis in the individual patients using laboratory studies and the clinical evaluation. ...

Background The pathogenesis of pulmonary fibrosis remains poorly understood. therefore theoretically avoiding ligand-receptor discussion. Frizzled-related proteins (FRZB) was the founding person in this family members [16-18] and verified to bind xWNT8 and antagonize its activity in and versions, including the impact caused by lack of endogenous SFRP1 and FRZB in the bleomycin-induced lung fibrosis model. We display that both and so are upregulated during bleomycin-induced lung fibrosis. to review their powerful profile in the bleomycin-induced pulmonary fibrosis model. and mRNA amounts had been 2 log-scales even more abundant than those of and may not be recognized. amounts were significantly improved at all period factors after bleomycin treatment however, not different between period points (Shape?1C) (2-method ANOVA PBS, 0.05 for period and connections). amounts were considerably and consistently elevated as time passes after bleomycin treatment (2-method ANOVA 0.0001 for bleomycin PBS, and ...

Purposes: Intestinal complications after radiotherapy are caused by transmural fibrosis and impair the quality of life of cancer survivors. Radiation fibrosis was considered permanent and irreversible, but recently, its dynamic nature was shown, providing new opportunities for the development of antifibrotic therapies. Among these new targets, we identified the Rho/ROCK pathway and thought to investigate whether pravastatin treatment inhibits Rho pathway activation and elicits an antifibrotic action. Experimental Design: Rho and ROCK activities were monitored in human explants presenting radiation fibrosis remodeling after incubation with pravastatin. Subsequent modulation of CCN2, type I collagen, and fibronectin expression were assessed ex vivo and in intestinal smooth muscle cells derived from radiation enteropathy. Then, the therapeutic relevance of the antifibrotic action of pravastatin was explored in vivo in a rat model of chronic radiation fibrosis (19 Gy X-rays) treated with 30 mg/kg/d ...

TY - JOUR. T1 - Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction. AU - Miyajima, Akira. AU - Chen, Jie. AU - Lawrence, Cathy. AU - Ledbetter, Steve. AU - Soslow, Robert A.. AU - Stern, Joshua. AU - Jha, Sharda. AU - Pigato, Joseph. AU - Lemer, Matthew L.. AU - Poppas, Dix P.. AU - Vaughan, E. Darracott. AU - Felsen, Diane. PY - 2000/1/1. Y1 - 2000/1/1. N2 - Background. Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-β (TGF-β), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-β (1D11) in UUO. Methods. Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day ...

TY - JOUR. T1 - M2 macrophage polarization modulates epithelial-mesenchymal transition in cisplatin-induced tubulointerstitial fibrosis. AU - Yu, Chia Cherng. AU - Chien, Chiang Ting. AU - Chang, Tzu Ching. PY - 2016/3/1. Y1 - 2016/3/1. N2 - Cisplatin-induced nephrotoxicity leaded to apoptosis of tubular epithelial cells (ECs) and tubulointerstitial fibrosis through ROS stress and inflammatory cytokines. Tubulointerstitial fibrosis caused by cisplatin might be via activation of resident fibroblasts and epithelial-mesenchymal transition (EMT) of tubular ECs. Inflammatory niche was crucial for progression of fibroblast activation or EMT. It had been reported that M1/M2 macrophage polarization regulated pro-inflammation or pro-resolving phase in damage repairing. However, the role of macrophage polarization on cisplatin-induced EMT of tubular ECs had not been well elucidated. In this study, we used co-cultured cell model and condition medium to examine the interaction between tubular ECs, ...

Interstitial fibrosis and tubular atrophy (IFTA), previously known as chronic allograft nephropathy (CAN), is diagnosed by pathologic changes involving all parts of the renal parenchyma and is one of the factors impacting graft survival and outcome. Currently, there is no standard to predict allograft fibrosis status at the time of procurement. Noninvasive biomarkers are necessary to monitor allograft status and to predict long-term outcomes.. The investigators aim to conduct a multicenter prospective study to identify urinary exosomal biomarkers that represent the extent of graft fibrosis from deceased donor kidney transplantation. Urinary samples will be collected from deceased kidney donors at the time of procurement and zero-day kidney graft biopsy will be performed at the time of transplant. The zero-day biopsy tissue will be stained with Massons Trichrome staining, Collagen I, III, IV immunostaining to evaluate the degree of fibrosis. Also, by ultracentrifuge, we will extract urinary ...

We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in renal fibrosis development. However, renal tubular epithelial cell-specific (RTEC-specific) HIPK2 function in renal fibrogenesis has yet to be determined. Here, we show that modulation of tubular HIPK2 expression and activity affects renal fibrosis development in vivo. The loss of HIPK2 expression in RTECs resulted in a marked diminution of renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and HIV-associated nephropathy (HIVAN) mouse models, which was associated with the reduction of Smad3 activation and downstream expression of profibrotic markers. Conversely, WT HIPK2 overexpression in RTECs accentuated the extent of renal fibrosis in the setting of UUO, HIVAN, and folic acid-induced nephropathy in mice. Notably, kinase-dead HIPK2 mutant overexpression or administration of BT173, an allosteric inhibitor of ...

TY - JOUR. T1 - Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. AU - Ko, Gang Jee. AU - Boo, Chang Su. AU - Jo, Sang Kyung. AU - Cho, Won Yong. AU - Kim, Hyoung Kyu. PY - 2008/3/1. Y1 - 2008/3/1. N2 - Background. Ischaemia/reperfusion is a major cause of acute kidney injury and can result in poor long-term graft function. Although most of the patients with acute kidney injury recover their renal function, significant portion of patients suffer from progressive deterioration of renal function. A persistent inflammatory response might be associated with long-term changes following acute ischaemia/reperfusion. Macrophages are known to infiltrate into tubulointersitium in animal models of chronic kidney disease. However, the role of macrophages in long-term changes after ischaemia/reperfusion remains unknown. We aimed to investigate the role of macrophages on the development of tubulointerstitial fibrosis and functional ...

Cystic fibrosis related diabetes (cfrd) cfrd is often treated with insulin. cystic fibrosis related diabetes (cfrd) refers to a form of diabetes as a direct consequence of having cystic fibrosis. diabetes is a common complication of cystic fibrosis with around 40-50% of adults with cystic fibrosis developing diabetes.. Cystic fibrosis-related diabetes (cfrd) is a unique type of diabetes that only people with cystic fibrosis develop. cfrd is similar to, but not the same as, diabetes in people who do not have cystic fibrosis. consequently, treatment of cfrd is not the same as treatment of other types of diabetes.. @ cystic fibrosis diabetes ★★ treating diabetes theres an app for that the 3 step trick that reverses diabetes permanently in as little as 11 days.[ cystic.. Cystic fibrosis-related diabetes (cfrd) is a unique type of diabetes that only people with cystic fibrosis develop. cfrd is similar to, but not the same as, diabetes in people who do not have cystic fibrosis. consequently, ...

Background: Aortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal post-aortic valve replacement (AVR). Methods: Asymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement [LGE]) were quantified. RESULTS: In 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 [26%]; LGE mass, 2.5 g [0.8-4.8 g]) demonstrated particularly ...

Results We first studied PDE4 inhibition by rolipram in a preventive bleomycin model. In this model, rolipram reduced skin thickening by 33% (p ,0.001), the amount of fibrotic tissue assessed by histomorphometry by 38% (p =0.016) and the number of α-SMA-positive myofibroblasts by 45% (p ,0.001). We then wondered if the clinically approved PDE inhibitor apremilast did also show significant anti-fibrotic activity, and if PDE inhibition did not only prevent but also treat fibrosis once it was established. In a modified bleomycin model of established fibrosis, apremilast reduced skin thickness by 26% (p=0.001) the amount of fibrotic tissue by 21% (p=0.037) and the number of myofibroblasts by 73% (p=0.001). Taking advantage of a model of cGvHD, we investigated if PDE4 blockade could also reduce fibrosis in a model for systemic fibrotic disease. Indeed, rolipram reduced skin thickness by 33% (p =0.002), the amount of fibrotic tissue by 35% (p=0.016) and of the number of α-SMA-positive myofibroblasts ...

miRNAs (microRNAs) have been shown to play a role in myocardial fibrosis. The present study was designed to analyse whether alterations in miRNA expression contribute to the progression of myocardial fibrosis in AS (aortic valve stenosis) patients through up-regulation of the pro-fibrotic factor TGF-β1 (transforming growth factor-β type 1). Endomyocardial biopsies were obtained from 28 patients with severe AS, and from the necropsies of 10 control subjects. AS patients presented increased myocardial CVF (collagen volume fraction) and TGF-β1 compared with the controls, these parameters being correlated in all patients. Patients were divided into two groups by cluster analysis according to their CVF: SF (severe fibrosis; CVF ,15%; n=15) and non-SF (CVF ≤15%; n=13). TGF-β1 was increased in patients with SF compared with those with non-SF. To analyse the involvement of miRNAs in SF, the miRNA expression profile of 10 patients (four with non-SF and six with SF) was analysed showing that 99 ...

Activated myofibroblasts are key effector cells in tissue fibrosis. staining for α-easy muscle actin identifies myofibroblasts in the infarcted heart. These cells are localized in the infarct border zone (lineage is the main source of matrix-secreting fibroblasts in normal skin in healing cutaneous wounds in radiation injury and in the stroma of melanomas [28?]. Ablation of these highly fibrogenic cells that expressed CD26 significantly reduced scarring following cutaneous injury and delayed growth of melanomas. In several different organs perivascular cells serve as important sources of activated myofibroblasts [26 Golvatinib 29 30 Pericytes are defined as perivascular cells of mesenchymal origin which are sheathed with a basement membrane and directly communicate with endothelial cells [31]. Studies in experimental models of kidney fibrosis have suggested that pericytes may be a major source of myofibroblasts [26 30 Recent investigations have indicated a broader role for perivascular cells in ...

IgA nephropathy (IgAN) is the commonest global cause of glomerulonephritis. Extent of fibrosis, tubular atrophy and glomerulosclerosis predict renal function decline. Extent of renal fibrosis is assessed with renal biopsy which is invasive and prone to sampling error. We assessed the utility of non-contrast native T1 mapping of the kidney in patients with IgAN for assessment of renal fibrosis. Renal native T1 mapping was undertaken in 20 patients with IgAN and 10 healthy subjects. Ten IgAN patients had a second scan to assess test-retest reproducibility of the technique. Native T1 times were compared to markers of disease severity including degree of fibrosis, eGFR, rate of eGFR decline and proteinuria. All patients tolerated the MRI scan and analysable quality T1 maps were acquired in at least one kidney in all subjects. Cortical T1 times were significantly longer in patients with IgAN than healthy subjects (1540 ms ± 110 ms versus 1446 ± 88 ms, p = 0.038). There was excellent test-retest

Renal fibrosis represents a final common outcome of many renal diseases and has attracted a great deal of attention. To better understand whether lncRNAs could be a player in this process or be a biomarker for renal fibrosis diagnosis, we compared transcriptome sequencing data on renal tissues and urine respectively between UUO (unilateral ureteral obstruction) and shamed (Sham) rat model. Numerous genes including lncRNAs with significant changes in their expression were identified. 24 lncRNAs were up-regulated and 79 lncRNAs were down-regulated in the renal tissues of the UUO rats. 625 lncRNAs were up-regulated and 177 lncRNAs were down-regulated in urines of the UUO rats. Among the lncRNAs upregulated in renal tissue of UUO rats, 19 lncRNAs were predicted containing several conserved Smad3 binding motifs in the promoter. Among them, lncRNAs with putative promoter containing more than 4 conserved Smad3 binding motifs were demonstrated to be induced by TGF-β significantly in normal rat renal tubular

RATIONALE: Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly. OBJECTIVES: To assess the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice. METHODS: Fibrosis progression in response to Streptococcus pneumoniae was examined in two different mouse models of pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-beta1 (TGFss1) or diphteria toxin (DT) treatment of transgenic mice expressing the DT receptor (DTR) under control of the surfactant protein C (SPC) promoter (SPC-DTR) to induce pulmonary fibrosis developed progressive fibrosis following infection with Spn, without exhibiting impaired lung protective immunity against Spn. Antibiotic treatment abolished infection-induced fibrosis progression. The cytotoxin pneumolysin (Ply) of Spn caused this ...

WHAT IS CYSTIC FIBROSIS?. Cystic fibrosis primarily affects the lungs and digestive system because of a malfunction in the exocrine system thats responsible for producing saliva, sweat, tears and mucus. There is currently no cure.​ People with cystic fibrosis develop an abnormal amount of excessively thick and sticky mucus within the lungs, airways and the digestive system. This causes impairment of the digestive functions of the pancreas and traps bacteria in the lungs resulting in recurrent infections, leading to irreversible damage. Lung failure is the major cause of death for someone with cystic fibrosis. From birth, a person with cystic fibrosis undergoes constant medical treatments and physiotherapy. ​. Cystic Fibrosis Queensland is the peak community, not-for-profit organisation working with and for people with cystic fibrosis. Its mission is to assist everyone affected by cystic fibrosis to be well and live fuller lives. It provides information, support and guidance to people living ...

This program explains Cystic Fibrosis. Cystic Fibrosis is also known as CF. The program includes the following sections: what is cystic fibrosis, what are the causes of cystic fibrosis, what are the symptoms of cystic fibrosis, how is cystic fibrosis diagnosed, what are treatment options for cystic fibrosis, and what are facts about cystic fibrosis.

BACKGROUND Polymorphisms in transforming growth factor (TGF)-β1 associated with variations in cytokine levels are linked to fibrosis in a number of tissues. However, the contribution of this cytokine to organ fibrosis in patients with cystic fibrosis is presently unclear. This study was undertaken to examine the association between TGF-β1 gene polymorphisms and the development of pulmonary dysfunction in patients with cystic fibrosis.. METHODS Polymorphisms in the TGF-β1 gene defining amino acids of codons 10 and 25 were determined by ARMS-PCR using DNA stored on 171 Caucasian patients who were homozygous for the ΔF508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical information on the patients was obtained from medical records.. RESULTS Patients with cystic fibrosis of a TGF-β1 high producer genotype for codon 10 had more rapid deterioration in lung function than those with a TGF-β1 low producer genotype. The relative risk of accelerated decline in ...

Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor β (TGF-β) signaling and the canonical WNT/β-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative

Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in nonalcoholic steatohepatitis (NASH). We evaluated the safety and anti-fibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH.We conducted two randomized, double-blind, placebo-controlled, phase 3 trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and noninvasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with 1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events.Neither trial met the primary ...

Kallistatin is a multiple functional serine protease inhibitor that protects against vascular injury, organ damage and tumor progression. Kallistatin treatment reduces inflammation and fibrosis in the progression of chronic kidney disease (CKD), but the molecular mechanisms underlying this protective process and whether kallistatin plays an endogenous role are incompletely understood. In the present study, we observed that renal kallistatin levels were significantly lower in patients with CKD. It was also positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with serum creatinine level. Unilateral ureteral obstruction (UUO) in animals also led to down-regulation of kallistatin protein in the kidney, and depletion of endogenous kallistatin by antibody injection resulted in aggravated renal fibrosis, which was accompanied by enhanced Wnt/β-catenin activation. Conversely, overexpression of kallistatin attenuated renal inflammation, interstitial fibroblast ...

TY - JOUR. T1 - Myocardial extracellular volume quantified by magnetic resonance is increased in cirrhosis and related to poor outcome. AU - Wiese, Signe. AU - Hove, Jens. AU - Mo, Silje. AU - Mookerjee, Rajeshwar P. AU - Petersen, Claus L. AU - Vester-Andersen, Marianne K. AU - Mygind, Naja D. AU - Goetze, Jens P. AU - Kjaer, Andreas. AU - Bendtsen, Flemming. AU - Møller, Søren. N1 - This article is protected by copyright. All rights reserved.. PY - 2018. Y1 - 2018. N2 - BACKGROUND & AIMS: The underlying pathogenesis of cirrhotic cardiomyopathy is unclear. Structural myocardial changes including diffuse fibrosis may be involved and can be accurately assessed by cardiac MRI (CMR) with quantification of the extracellular volume (ECV).This is the first application of this technique in patients with cirrhosis. We aimed to investigate the presence of diffuse myocardial fibrosis and to determine the relation to disease severity, cardiac function, and outcome.METHODS: A prospective study including ...

Keywords: Human being BM- and WJ-MSCs, Liver organ fibrosis, MMPs, Angiogenesis Background Liver organ fibrosis/cirrhosis can be a main wellness issue world-wide and, among the 1.4 million liver organ disease fatalities occurring each full year, 55% of these are attributed to liver organ cirrhosis [1, 2]. Liver organ fibrosis/cirrhosis-related fatality offers been gradually raising world-wide, as has alcohol consumption, and the prevalence of hepatitis B, C, and diabetes [3]. It has been reported that almost one-fifth (18.3%) of global liver fibrosis/cirrhosis deaths occur in India [3]. Currently, there is no effective treatment available to cure liver fibrosis/cirrhosis. Liver transplantation remains the only Rabbit Polyclonal to p38 MAPK (phospho-Thr179+Tyr181) option but this is hindered by a lack of donor organs and immune-rejection. Transplantation of adult hepatocytes is another alternative and has been used in clinical studies, predominantly in hereditary metabolic disorders [4, 5] or as ...

Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV

Herein, we demonstrate that 5-HT2B signaling plays a central role for fibrosis. Several experimental levels such as 5-HT2B-null mice and treatment with small molecule inhibitors as well as in vitro and ex vivo studies in humans suggested that binding of 5-HT to its receptor 5-HT2B is a key step in tissue fibrosis. We believe that these findings have direct clinical implications: potent inhibitors of 5-HT2 receptors, including cyproheptadine and terguride used in our study as well as mianserin and lisuride, are already in clinical use and are well tolerated (Obeso et al., 1986; von Werner et al., 1989; Moertel et al., 1991; Szegedi and Schwertfeger, 2005). Furthermore, selective inhibitors of 5-HT2B are in clinical development and might be available in the near future. Thus, inhibition of 5-HT2B might be a promising novel therapeutic approach as efficient antifibrotic therapies are not yet available.. Patients affected with SSc develop a characteristic microangiopathy as the result of ongoing ...

Circulation. 2012 Oct 2;126(14):1705-16. doi: 10.1161/CIRCULATIONAHA.111.075978. Epub 2012 Aug 29. Research Support, N.I.H., Extramural

New advances in cystic fibrosis medical research announced in June have been welcomed by the Cystic Fibrosis Trust as it stands to benefit up to half of all people living with cystic fibrosis in the UK.. The results, released by Vertex Pharmaceuticals Ltd, of a phase III trial for a new treatment for people with cystic fibrosis aged 12 and over with two copies of the F508del mutation, demonstrate that a combination of the drugs ivacaftor and lumacaftor could offer additional treatment to address the underlying cause of the disease and increase lung capacity.. Janet Allen, Director of Care and Research for the Cystic Fibrosis Trust said: We are pleased to see these promising results, which open up a new front in the fight against cystic fibrosis. This new combination therapy looks set to be an important additional treatment option that could improve the lives of many people with cystic fibrosis. As this leading edge of science continues to be explored and better understood, we are hopeful that a ...

Aims Epidemiological and interventional studies have suggested a protective role for vitamin D in cardiovascular disease, and basic research has implicated vitamin D as a potential inhibitor of fibrosis in a number of organ systems; yet little is known regarding direct effects of vitamin D on human cardiac cells. Given the critical role of fibrotic responses in end stage cardiac disease, we examined the effect of active vitamin D treatment on fibrotic responses in primary human adult ventricular cardiac fibroblasts (HCF-av), and investigated the relationship between circulating vitamin D (25(OH)D-3) and cardiac fibrosis in human myocardial samples. Methods and Results Interstitial cardiac fibrosis in end stage HF was evaluated by image analysis of picrosirius red stained myocardial sections. Serum 25(OH)D-3 levels were assayed using mass spectrometry. Commercially available HCF-av were treated with transforming growth factor (TGF)beta 1 to induce activation, in the presence or absence of active ...

The role of the immune response in lung fibrosis and its potential as therapeutic target are not clearly established. Here, we provide evidence for a functional contribution of Fra-2-expressing macrophages to the paracrine activation of fibroblasts and to lung fibrosis (Figure 8F). We identify ColVI as a Fra-2 transcriptional target in macrophages and unravel a profibrogenic role for ColVI in vitro and in vivo. Importantly, inhibiting Fra-2/AP-1 or ColVI is therapeutically relevant in mouse models of lung fibrosis.. The fibrotic phenotype in the Fra-2Tg model of fibrosis is reminiscent of a type 2 cytokine-driven disease with enhanced IL-4 expression, IL-4 pathway signature, eosinophil/neutrophil infiltration, and M(IL-4) macrophage enrichment (25, 28, 46). The contribution of type 2 cytokines, IL-4 and IL-13, to macrophage activation and fibrosis development in different organs is well accepted (4, 47, 48). Lung-specific expression of these cytokines increases after bleomycin treatment, ...

Hepatic fibrosis is suspected in patients who have an underlying disorder or take a drug that could cause fibrosis or who have unexplained abnormalities in liver function or enzymes. Noninvasive tests (eg, serologic markers) are under study but are not yet ready for routine clinical use. Imaging tests such as ultrasonography, CT, and MRI may detect findings associated with fibrosis (eg, portal hypertension, splenomegaly, cirrhosis) but are not sensitive to parenchymal fibrosis itself. Liver biopsy is currently the only means of detecting hepatic fibrosis. Biopsy is indicated to clarify the diagnosis (eg, nonalcoholic steatohepatitis, primary biliary cirrhosis) and stage its progress (eg, in chronic hepatitis C, whether fibrosis is present or whether it has progressed to cirrhosis).. ...

Cystic fibrosis (CF) is a genetic disease that causes problems with the ability of different organs in the body to work. More specifically, the buildup of sticky and thick mucus inside the lungs, pancreas, and other organs leads to frequent bacterial lung infections, reduced lung function, and chronic gastrointestinal (digestive) problems. Cystic fibrosis can also impact the liver and reproductive systems. Mucus is vital to lubricating and protecting the linings of the airways, digestive system, reproductive system, and other organs and tissues. In individuals with cystic fibrosis, the mucus that is produced is abnormally thick and sticky. This abnormal mucus can clog the airways, leading to severe problems with breathing and bacterial infections in the lungs. These chronic (constant) infections cause coughing, wheezing, and inflammation. Over time, mucus buildup and infections result in permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs; hence the ...

The physiological functions of LVs and their contributions to pathological mechanisms during chronic disease conditions have not been extensively investigated. We have addressed this gap in the context of CKD by comprehensively investigating the role of lymphangiogenesis in kidneys and RDLNs. We describe a previously unrecognized function of lymphangiogenesis as a key process in the kidney and RDLNs mediating intrarenal inflammation and progressive fibrosis. Although it has been previously reported that lymphangiogenesis is a common feature in the progression of renal fibrosis (19), the origin and function of intrarenal LVs in CKD remained undefined. Here, we observed extensive LEC proliferation in a cohort of 289 CKD patients that was not evident in healthy controls. CKD patients with higher density intrarenal LVs presented with more severe proteinuria and renal fibrosis and decreased eGFR. Our mouse model experiments revealed localized LEC proliferation as the cellular origin of ...

article: The effects of dietary intervention on fibrosis and biochemical parameters in metabolic-associated fatty liver disease - Minerva Gastroenterology 2021 Apr 08 - Minerva Medica - Journals

Myofibroblast transdifferentiation is now recognized as a hallmark event in the pathogenesis of cardiac fibrosis from a variety of cardiac diseases (15). While it is well recognized that these cells are hypersecretory for a number of key matrix proteins and that TGF-β/R-Smads are key mediators of cardiac fibrosis in heart failure etiologies (12, 22, 42), the study of endogenous Smad-associated proteins that may inhibit these profibrotic signals is in its infancy. We have previously described the antifibrotic actions of Smad7 in plated primary cardiac myofibroblasts, and its diminished expression in healing myocardial infarcts (49, 50), but the function(s) of other members of this unique group of proteins, e.g., c-Ski and Sno-N, remains unclear in this context. Furthermore, an understanding of the effects of c-Ski isoforms in cardiac fibroblasts may assist in determining the physiological role of this protein in healthy and diseased heart. Herein we have characterized the functional and ...

Cystic Fibrosis Defined - Diagnosis of Cystic Fibrosis, Causes and Risk Factors of Cystic Fibrosis, Genetic Testing, Symptoms of Cystic Fibrosis.

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BACKGROUND: The left ventricular (LV) dilatation of isolated mitral regurgitation (MR) is associated with an increase in chymase and a decrease in interstitial collagen and extracellular matrix. In addition to profibrotic effects, chymase has significant antifibrotic actions because it activates matrix metalloproteinases and kallikrein and degrades fibronectin. Thus, we hypothesize that chymase inhibitor (CI) will attenuate extracellular matrix loss and LV remodeling in MR. METHODS AND RESULTS: We studied dogs with 4 months of untreated MR (MR; n=9) or MR treated with CI (MR+CI; n=8). Cine MRI demonstrated a |40% increase in LV end-diastolic volume in both groups, consistent with a failure of CI to improve a 25% decrease in interstitial collagen in MR. However, LV cardiomyocyte fractional shortening was decreased in MR versus normal dogs (3.71±0.24% versus 4.81±0.31%; P CONCLUSIONS: These results suggest that chymase disrupts cell surface-fibronectin connections and FAK phosphorylation that can

The histopathologic features of hypertrophic cardiomyopathy (HCM) are left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis (1).. Cardiac magnetic resonance (CMR) is the gold standard for in vivo assessment of focal myocardial fibrosis using the late gadolinium enhancement (LGE) technique (2). This correlates with clinical risk factors for sudden death and arrhythmias, and is predictive of adverse outcomes including heart failure (3). It remains unclear how fibrosis evolves and how evolution correlates with ventricular remodeling. Our aim was to track long-term changes in CMR LGE in HCM over a 7-year follow-up period.. From 2001 to 2003, 59 patients with HCM (5 gene-positive for sarcomeric gene mutations with electrocardiogram changes fulfilling familial criteria) (1) underwent CMR LGE. Follow-up scans were performed in 12 patients on average 7.4 ± 0.4 years after the initial scans. The attrition of this overall high-risk cohort from a tertiary referral center occurred ...

Pulmonary fibrosis is more prevalent among men than it is among women. Adults between the ages of 40 and 70 have the highest risk, and approximately 65% of those affected by the condition are over the age of 60. Certain chemotherapy drugs and cardiac medications are potential risk factors, and these drugs are most commonly used by individuals in this age category. Some medical researchers believe that pulmonary fibrosis may begin as an inflammatory response. In tissues like the lungs that dont have the capacity to regenerate, inflammation can lead to scarring. Scar tissue cant support specialized cells, so functional impairment occurs. This theory appears to be supported by the fact that pulmonary fibrosis often arises in conjunction with autoimmune diseases like lupus erythematosus, rheumatoid arthritis, and scleroderma. There are also higher incidences of pulmonary fibrosis among individuals whove been exposed to environmental toxicants like cigarette smoke, asbestos fibers, radiation, and ...

A recent market study published by the company Pulmonary Fibrosis Treatment Market: Global Industry Analysis 2014-2018 & Forecast, 2019-2029 consists of a comprehensive assessment of the most important market dynamics. After conducting thorough research on the historic as well as current growth parameters of the pulmonary fibrosis treatment market, the growth prospects of the market can be obtained with maximum precision. The report features the unique and salient factors that are likely to significantly impact the development of the pulmonary fibrosis treatment market during the forecast period. It can help market players modify their manufacturing and marketing strategies to envisage maximum growth in the pulmonary fibrosis treatment market in the upcoming years. The report provides detailed information about the current and future growth prospects of the pulmonary fibrosis treatment market in the most comprehensive manner for the better understanding of readers.. Chapter 01 - Executive ...

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fibrosis (es); Fibrosi (eu); fibrosi (ca); Fibrose (de); فیبروز (fa); 纤维化 (zh); 線維化 (ja); Fibros (sv); Фіброз (uk); Fibrosis (la); 섬유화 (ko); fibrozo (eo); Fibróza (cs); இழைநார்ப் பெருக்கம் (ta); Fibrosi (it); Fibrose (fr); Fibroza (hr); Xơ hóa (vi); Fibroza (sr); Fibrose (gl); לייפת (he); Fibrosis (id); Fibrosi (pl); fibrose (pt); Fibrose (nl); фіброз (be-tarask); Fibroza (bs); Фиброз (ru); Фиброза (bg); fibrosis (en); تليف (ar); Fibrosis (ms); Fibroz (uz) formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process (en); Ehun bat zuntzezko ehun bilakatzean datzan fenomenoa (eu); formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process (en) 線維症, 抗線維化, 抗線維化作用, 線維形成性 (ja); 纖維結締組織 (zh); التليف (ar ...

Recruitment from the bone marrow, EMT and EndMT appear to rely on transforming growth factor beta 1 (TGF-B1) to differentiate into myofibroblasts.. Pericytes are not involved. Some earlier descriptive studies implicated pericytes - connective, contractile cells that surround blood vessels - in the creation of myofibroblasts. The researchers tested pericytes via fate-mapping and found that theyre not involved in myofibroblast generation.. Deleting pericytes did not improve kidney fibrosis or change the recruitment of myofibroblasts.. While their research focused on kidney fibrosis, the scientists believe their findings will be applicable to other types of fibrosis.. Recruitment of fibroblasts is heterogonous. The sources are likely to be the same for lung or liver fibrosis, but the ratios may be different, Kalluri said. Now we need to go into those other organs and establish a baseline of what were facing like we did in kidney fibrosis.. Kalluri holds the Rebecca Meyer Brown and Joseph ...

To investigate whether apocynin, a NADPH oxidase inhibitor, produced cardioproteictive effects in Ang II-induced hypertensive mice, and to elucidate the underlying mechanisms. C57BL/6 mice were subcutaneously infused Ang II for 4 weeks to mimic

Chronic kidney disease (CKD) is a leading cause of end stage renal disease (ESRD) and cardiovascular morbidity and mortality worldwide, resulting in a growing social and economic burden. The prevalence and burden of CKD is anticipated to further increase over the next decades as a result of aging. In the pathogenesis of CKD, irrespective of the etiology, resident fibroblasts are key players and have been demonstrated to play crucial roles for disease initiation and progression. In response to injury, resident fibroblasts transdifferentiate into myofibroblasts that express alpha smooth muscle actin (αSMA) and have an increased capacity to produce large amounts of extracellular matrix (ECM) proteins, leading to renal fibrosis. In addition to this fundamental role of fibroblasts as drivers for renal fibrosis, growing amounts of evidence have shown that resident fibroblasts are also actively involved in initiating and promoting inflammation during kidney injury. During the myofibroblastic transition