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1.
Mol Med Rep ; 23(2): 1, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33655326

RESUMO

Angiotensin II (AngII) is a central signaling molecule of the renin­angiotensin system that serves a vital role in myocardial fibrosis (MF). The present study aimed to investigate the effects of matrix metalloproteinase (MMP)3 on MF progression. To induce cellular fibrosis, H9C2 rat myocardial cells were treated with AngII for 24 h. Subsequently, cells were treated with levocarnitine, or transfected with small interfering (si)RNA­negative control or siRNA­MMP3 (1/2/3). Cell viability, apoptosis and migration were assessed by performing Cell Counting Kit­8, flow cytometry and Transwell assays, respectively. Reverse transcription­quantitative PCR (RT­qPCR) and western blotting were performed to determine the expression levels of MF biomarkers, including disease­, apoptosis­ and oxidative stress­related genes. Compared with the control group, AngII significantly inhibited H9C2 cell viability and migration, and significantly increased H9C2 cell apoptosis (P<0.05). However, compared with AngII­treated H9C2 cells, MMP3 knockdown significantly inhibited fibrotic H9C2 cell viability and migration, but increased fibrotic H9C2 cell apoptosis (P<0.05). The RT­qPCR results demonstrated that MMP3 knockdown significantly downregulated the expression levels of AXL receptor tyrosine kinase, AngII receptor type 1, α­smooth muscle actin and Collagen I in AngII­treated H9C2 cells (P<0.05). Moreover, compared with AngII­treated cells, MMP3 knockdown significantly decreased Bcl­2 expression levels , but significantly increased caspase­3 and p53 expression levels in AngII­treated cells (P<0.05). Additionally, compared with AngII­treated cells, MMP3 knockdown significantly decreased MMP3, MMP9, STAT3, p22Phox and p47Phox expression levels in AngII­treated cells (P<0.05). The present study indicated that MMP3 knockdown altered myocardial fibroblast cell viability, migration and apoptosis by regulating apoptosis­ and oxidative stress­related genes, thus delaying MF progression.


Assuntos
Angiotensina II/farmacologia , Apoptose , Fibrose/genética , Coração/fisiopatologia , Metaloproteinase 3 da Matriz/metabolismo , Angiotensina II/metabolismo , Animais , Movimento Celular , Sobrevivência Celular , Células Cultivadas , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fibrose/fisiopatologia , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Ratos , Transdução de Sinais
2.
Methods Mol Biol ; 2193: 13-21, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32808254

RESUMO

The ideal response to skin injury is the complete regeneration of normal tissue without scar formation. This regenerative response is known to occur at early stages of embryonic development but is lost as the skin becomes more mature. In more developed skin, the wound-healing response is suboptimal and results in the formation of scar tissue. Scar tissue can be a significant clinical concern, causing skin dysfunction as well as psychosocial issues related to poor aesthetic outcomes. Mouse models of fetal wound healing can be useful for understanding what regulatory pathways lead to skin regeneration and scarless healing in less developed skin or scarring and fibrotic healing in more developed skin. Here, a reproducible incisional wound model in developing mice is described that our lab has used repeatedly to study scarless and fibrotic fetal wound healing.


Assuntos
Fibrose/fisiopatologia , Biologia Molecular/métodos , Regeneração/fisiologia , Cicatrização/fisiologia , Animais , Cicatriz/fisiopatologia , Modelos Animais de Doenças , Feminino , Feto/fisiologia , Humanos , Camundongos , Gravidez , Pele/fisiopatologia
3.
PLoS One ; 15(12): e0244282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33351821

RESUMO

PURPOSE: Cardiac involvement in Systemic Sclerosis (SSc) is increasingly recognized as a mayor cause of morbidity and mortality. The aim of present study is to investigate the early stages of cardiac involvement in SSc by Cardiovascular magnetic resonance (CMR), combining the non-invasive detection of myocardial inflammation and fibrosis using T2 and T1 mapping techniques and the assessment of microcirculatory impairment through perfusion response to cold pressor test (CPT). METHODS: 40 SSc patients (30 females, mean age: 42.1 years) without cardiac symptoms and 10 controls underwent CMR at 1.5 T unit. CMR protocol included: native and contrast-enhanced T1 mapping, T2 mapping, T2-weighted, cineMR and late gadolinium enhancement (LGE) imaging. Microvascular function was evaluated by comparing myocardial blood flow (MBF) on perfusion imaging acquired at rest and after CPT. Native myocardial T1 and T2 relaxation times, extracellular volume fraction (ECV), T2 signal intensity ratio, biventricular volumes and LGE were assessed in each patient. RESULTS: SSc patients had significantly higher mean myocardial T1 (1029±32ms vs. 985±18ms, p<0.01), ECV (30.1±4.3% vs. 26.7±2.4%, p<0.05) and T2 (50.1±2.8ms vs. 47±1.5ms, p<0.01) values compared with controls. No significant differences were found between absolute MBF values at rest and after CPT; whereas lower MBF variation after CPT was observed in SSc patients (+33 ± 14% vs. +44 ± 12%, p<0.01). MBF variation had inverse correlation with native T1 values (r: -0.32, p<0.05), but not with ECV. CONCLUSIONS: Myocardial involvement in SSc at preclinical stage increases native T1, T2 and ECV values, reflecting inflammation and fibrosis, and reduces vasodilatory response to CPT, as expression of microvascular dysfunction.


Assuntos
Microcirculação/fisiologia , Miocardite/patologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Doenças Assintomáticas , Estudos de Casos e Controles , Meios de Contraste , Feminino , Fibrose/fisiopatologia , Humanos , Imagem por Ressonância Magnética/métodos , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Miocardite/diagnóstico por imagem , Miocárdio/patologia , Miócitos Cardíacos/patologia , Estudos Prospectivos , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/metabolismo , Função Ventricular Esquerda/fisiologia
4.
Ann Agric Environ Med ; 27(4): 568-573, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33356062

RESUMO

INTRODUCTION: Alcohol consumption causes acute and chronic liver injury. The clinical forms of alcohol liver disease (ALD) include steatosis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) associated with liver cirrhosis. OBJECTIVE: The aim of the study was to determine the levels of novel markers of fibrogenesis and angiogenesis in patients with alcoholic liver cirrhosis. Serum levels of angiopoietin-like peptide 4 (ANGPTL-4), asialoglycoprotein receptor 1 (ASGP-R1), and S100 calcium-binding protein A8 (S100A8) were assessed. Levels of hyaluronic acid (Hyal) and collagen IV (Coll IV) werealso determined at various stages of alcoholic liver cirrhosis. MATERIAL AND METHODS: The study group consisted of 72 patients with alcoholic liver cirrhosis, while the control group included 22 healthy subjects without a history of alcohol abuse. The degree of liver cirrhosis was evaluated according to the Pugh-Child criteria (Pugh-Child score). Based on thse scores, patients were assigned to one of three groups: Pugh-Child (P-Ch) A - 21 with stage A, P-Ch B - 23 with stage B and P-Ch C - 28 with stage C liver cirrhosis. Serum levels of markers were determined using ELISA. RESULTS: The study findings demonstrated higher levels of ANGPTL-4, ASGP-R1, S100A, hyaluronic acid and serum collagen IV in the group of patients with alcoholic liver cirrhosis, compared to the control group. Furthermore, their levels increased with the progression of alcoholic liver cirrhosis. CONCLUSIONS: The biomarkers analysed in the study may be useful for diagnosis and prognosis in patients with alcoholic liver cirrhosis.


Assuntos
Biomarcadores/sangue , Fibrose/fisiopatologia , Cirrose Hepática Alcoólica/complicações , Neovascularização Patológica/fisiopatologia , Adulto , Idoso , Feminino , Fibrose/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Polônia
5.
Proc Natl Acad Sci U S A ; 117(34): 20741-20752, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788346

RESUMO

Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-ß1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-ß1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.


Assuntos
Proteína Smad3/metabolismo , Fator de Transcrição Brn-3A/genética , Fator de Crescimento Transformador beta1/metabolismo , Animais , Feminino , Fibrose/fisiopatologia , Redes Reguladoras de Genes , Humanos , Inflamação/patologia , Rim/patologia , Nefropatias/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Transdução de Sinais/genética , Fator de Transcrição Brn-3A/metabolismo , Fator de Transcrição Brn-3A/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Sistema Urinário/metabolismo
6.
Life Sci ; 254: 117783, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32413404

RESUMO

AIMS: This study aimed to examine the anti-fibrotic role of Nuclear Factor-Erythroid derived 2 (NF-E2) in human renal tubule (HK-11) cells and in type 1 and type 2 diabetic (T1D, T2D) mouse kidneys. MAIN METHODS: Anti-fibrotic effects of NF-E2 were examined in transforming growth factor-ß (TGF-ß) treated HK-11 cells by over-expressing/silencing NF-E2 expression and determining its effects on profibrotic signaling. NF-E2 proteasomal degradation was confirmed by proteasome inhibition in HK-11 cells and diabetic mice. Clinical relevance of changes in NF-E2 expression to fibrotic changes in the kidney were assessed in T1D and T2D mouse kidneys. KEY FINDINGS: NF-E2 expression was significantly decreased in TGF-ß treated HK-11 cells and in kidneys of diabetic mice with concurrent increase in expression of fibrotic proteins. TGF-ß treatment of HK-11 cells did not inhibit NF-E2 mRNA expression, suggesting that the post-translational changes may contribute to NF-E2 protein degradation. The down-regulation of NF-E2 expression was attributed to its proteasomal degradation, as TGF-ß- and diabetes-induced NF-E2 down regulation was prevented by proteasome inhibitor treatment. In HK-11 cells TGF-ß treatment decreased E-cadherin expression and induced pSer82Hsp27/NF-E2 association, likely to promote NF-E2 degradation, as Hsp27 can target proteins to the proteasome. A critical role for NF-E2 in regulation of renal fibrosis was demonstrated as over-expression of NF-E2 or silencing NF-E2 expression, decreased or increased profibrotic proteins in TGF-ß-treated HK-11 cells, respectively. SIGNIFICANCE: NF-E2, a novel anti-fibrotic protein, is down-regulated in diabetic kidneys. Preserving/inducing NF-E2 expression in diabetic kidneys may provide a therapeutic potential to combat DN.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Fibrose/fisiopatologia , Subunidade p45 do Fator de Transcrição NF-E2/fisiologia , Animais , Caderinas/biossíntese , Células Cultivadas , Inibidores de Cisteína Proteinase/farmacologia , Diabetes Mellitus Experimental/genética , Regulação para Baixo , Fibrose/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Rim/metabolismo , Túbulos Renais/metabolismo , Leupeptinas/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Subunidade p45 do Fator de Transcrição NF-E2/biossíntese , Subunidade p45 do Fator de Transcrição NF-E2/genética , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/efeitos adversos , Fator de Crescimento Transformador beta/antagonistas & inibidores
7.
BMC Health Serv Res ; 20(1): 335, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32316984

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in Australia and its recent increase mirrors the obesity and type 2 diabetes epidemics. Currently, many patients who present to primary care with abnormal liver function tests or steatosis on liver ultrasound are referred for assessment in secondary care. Due to the large number of patients with NAFLD, this results in long waits for clinical and fibrosis assessment, placing unnecessary burden on the public hospital system. METHODS: We will conduct a 1:1 parallel randomised trial to compare two alternative models of care for NAFLD. Participants will be randomised to usual care or the LOCal Assessment and Triage Evaluation (LOCATE) model of care and followed for 1 year. We will recruit patients from the non-neighbouring Sunshine Coast and Metro South Hospital and Health Services (HHSs) in Queensland, Australia. Our primary outcome of interest is time to diagnosis of high-risk NAFLD, based on the number of participants in each arm of the study who receive a diagnosis of clinically significant fibrosis. Two hundred and 34 participants will give us a 95% power to detect a 50% reduction in the primary outcome of time to diagnosis of high-risk disease. We will also conduct an economic evaluation, evaluating the cost-effectiveness of the new model of care. We will also evaluate the implementation of the new model of care. DISCUSSION: It is anticipated that the results of this study will provide valuable new information regarding the management of NAFLD in the Australian setting. A relatively simple change to care could result in earlier identification of patients with significant liver disease and lower overall costs for the health system. Results will be directly disseminated to key staff for further distribution to consumers, policy- and decision-makers in the form of evidence briefs, plain language summaries and policy recommendations. TRIAL REGISTRATION: The trial was registered on 30 January, 2020 and can be found via ANZCTR - number ACTRN12620000158965.


Assuntos
Serviços de Saúde Comunitária , Hepatopatia Gordurosa não Alcoólica/patologia , Projetos de Pesquisa , Triagem , Austrália , Análise Custo-Benefício , Diabetes Mellitus Tipo 2 , Feminino , Fibrose/diagnóstico , Fibrose/fisiopatologia , Pesquisa sobre Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Queensland , Medição de Risco
8.
Dig Dis Sci ; 65(7): 1904-1916, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32279173

RESUMO

Despite recent advances aimed to treat transmural inflammation in Crohn's disease (CD) patients, the progression to a structuring behavior still represents an issue for clinicians. As inflammation becomes chronic and severe, the attempt to repair damaged tissue can result in an excessive production of extracellular matrix components and deposition of connective tissue, thus favoring the formation of strictures. No specific and accurate clinical predictors or diagnostic tools for intestinal fibrosis exist, and to date, no genetic or serological marker is in routine clinical use. Therefore, intestinal fibrosis is usually diagnosed when it becomes clinically evident and strictures have already occurred. Anti-fibrotic agents such as tranilast, peroxisome proliferator-activated receptor gamma agonists, rho kinase inhibitors, and especially mesenchymal stem cell therapy have provided interesting results, but most of the evidence has been derived from studies performed in vitro. Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures. Although its long-term outcomes may be debated, endoscopic balloon dilation appears to be the safest and most effective approach to treat appropriately selected strictures. The use of endoscopic stricturotomy is currently limited by the expertise needed to perform it and by the few data available in the literature. Some good results have been achieved by the positioning of self-expandable metal stents (SEMS). However, there is no concordance regarding the type of stent to use and for how long it should be left in place. The development of new specific SEMS may lead to better outcomes and to an increased use of this alternative in CD-related strictures.


Assuntos
Constrição Patológica/fisiopatologia , Constrição Patológica/terapia , Doença de Crohn/fisiopatologia , Endoscopia Gastrointestinal , Intestinos/patologia , Stents Metálicos Autoexpansíveis , Anti-Inflamatórios não Esteroides/uso terapêutico , Constrição Patológica/etiologia , Constrição Patológica/metabolismo , Doença de Crohn/complicações , Doença de Crohn/metabolismo , Doença de Crohn/terapia , Dilatação , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrose/metabolismo , Fibrose/fisiopatologia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , PPAR gama/agonistas , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , ortoaminobenzoatos/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores
9.
Arterioscler Thromb Vasc Biol ; 40(4): 958-972, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32078339

RESUMO

OBJECTIVE: Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells (Fstl1ECKO) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with Fstl1 knockout in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of Fstl1ECKO mutants. The SMAD3 (mothers against decapentaplegic homolog 3) phosphorylation (pSMAD3) was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFß (transforming growth factor ß) signaling in vascular mural cells of Fstl1ECKO mice. Consistently, treatment with a TGFß pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels in Fstl1ECKO mutant mice. CONCLUSIONS: The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.


Assuntos
Endotélio Vascular/fisiopatologia , Fibrose/fisiopatologia , Proteínas Relacionadas à Folistatina/fisiologia , Proteína Smad3/fisiologia , Actinas/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/fisiologia , Proteínas Relacionadas à Folistatina/metabolismo , Homeostase , Humanos , Camundongos Knockout , Fosforilação , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Insuficiência da Valva Tricúspide/fisiopatologia , Resistência Vascular
10.
Exp Mol Pathol ; 114: 104409, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32088192

RESUMO

BACKGROUND: Noise is an important environmental risk factor. Industrial environments are rich in high-intensity infrasound (hi-IFS), which we have found to induce myocardial and coronary perivascular fibrosis in rats. The effects of exposure to IFS on the ventricles have been studied, but not on the atria. We hypothesized that rats exposed to hi-IFS develop atrial remodeling involving fibrosis and connexin 43, which we sought to evaluate. MATERIAL AND METHODS: Seventy-two Wistar rats, half exposed to hi-IFS (120 dB, <20 Hz) during a maximum period of 12 weeks and half age-matched controls, were studied. Atrial fibrosis was analyzed by Chromotrope-aniline blue staining. The immunohistochemical evaluation of Cx43 was performed using the polyclonal antibody connexin-43 m diluted 1:1000 at 4 °C overnight. Digitized images were obtained with an optical microscope using 400× magnifications. The measurements were performed using image J software. A two-way ANOVA model was used to compare the groups. RESULTS: The mean values of the ratio "atrial fibrosis / cardiomyocytes" increased to a maximum of 0.1095 ± 0,04 and 0.5408 ± 0,01, and of the ratio "CX43 / cardiomyocytes" decreased to 0.0834 ± 0,03 and 0.0966 ± 0,03, respectively in IFS-exposed rats and controls. IFS-exposed rats exhibited a significantly higher ratio of fibrosis (p < .001) and lower ratio of Cx43 (p = .009). CONCLUSION: High-intensity infrasound exposure leads to an increase in atrial interstitial fibrosis and a decrease in connexin 43 in rat hearts. This finding reinforces the need for further experimental and clinical studies concerning the effects of exposure to infrasound.


Assuntos
Conexina 43/genética , Fibrose/genética , Coração/fisiopatologia , Ruído/efeitos adversos , Animais , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/fisiopatologia , Regulação da Expressão Gênica/efeitos da radiação , Coração/efeitos da radiação , Átrios do Coração/fisiopatologia , Átrios do Coração/efeitos da radiação , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Wistar , Fatores de Risco
11.
J Biomed Sci ; 27(1): 34, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059667

RESUMO

BACKGROUND: In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as "point of no return" leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney. METHODS: Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy. RESULTS: Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-ß1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia. CONCLUSIONS: This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as "point of no return" leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury.


Assuntos
Inflamação/fisiopatologia , Necrose Tubular Aguda/patologia , Rim/patologia , Traumatismo por Reperfusão/patologia , Animais , Atrofia/patologia , Atrofia/fisiopatologia , Biomarcadores/metabolismo , Fibrose/patologia , Fibrose/fisiopatologia , Inflamação/patologia , Rim/fisiopatologia , Necrose Tubular Aguda/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/fisiopatologia
12.
Sci Rep ; 10(1): 2561, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054932

RESUMO

The clinical assessment of fibrosis is critical to the diagnosis and management of patients with systemic sclerosis. Current clinical standards for patient assessment is to use skin fibrosis as an indicator of organ involvement, though this approach is highly subjective and relies on manual palpation. The development of a new method for accurately quantifying collagen content may therefore significantly improve the accuracy of the traditional skin score in patients with systemic sclerosis and may additionally aid in the monitoring of anti-fibrotic therapies in clinical practice. Polarization-sensitive optical coherence tomography (PS-OCT) is a high-speed volumetric imaging modality that can be used to assess birefringent tissues including collagen. In this work we demonstrate a novel computational approach using PS-OCT for the assessment of fibrosis. This approach, based on the measured distribution of optic axis values associated with a given volume of collagen orientation, characterizes fibrotic changes independently from the depth of the region of interest in the tissue. This approach has the potential to accurately quantify collagen content and orientation faster and more robustly compared to traditional PS-OCT metrics. We investigate the viability of this approach for assessing the development of fibrosis in a bleomycin induced skin fibrosis mouse model.


Assuntos
Olho/fisiopatologia , Processamento de Imagem Assistida por Computador/métodos , Escleroderma Sistêmico/fisiopatologia , Tomografia de Coerência Óptica/métodos , Animais , Bleomicina/toxicidade , Colágeno/metabolismo , Colágeno/ultraestrutura , Progressão da Doença , Olho/diagnóstico por imagem , Fibrose/induzido quimicamente , Fibrose/diagnóstico por imagem , Fibrose/fisiopatologia , Humanos , Camundongos , Refração Ocular/fisiologia , Escleroderma Sistêmico/diagnóstico por imagem
13.
Med Sci Monit ; 26: e918883, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974331

RESUMO

BACKGROUND The structural remodeling of atrial architecture, especially increased amounts of fibrosis, is a critical substrate to atrial fibrillation (AF). Doxycycline (Doxy) has recently been shown to exert protective effects against fibrogenic response. This study investigated whether doxycycline (Doxy) can sufficiently ameliorate the fibrosis-induced changes of atrial conduction and AF vulnerability in a chronic intermittent hypoxia (CIH) rat model. MATERIAL AND METHODS Sixty rats were randomized into 3 groups: Control, CIH, and CIH with Doxy treatment (DOXY) group. CIH rats were exposed to CIH (6 h/d) and Doxy-treated rats were treated with Doxy during processing CIH. After 6 weeks, echocardiographic and hemodynamic parameters were measured. Isolated atrial epicardial activation mapping and heart electrophysiology were performed. The extent of atrial interstitial fibrosis were estimated by Masson's trichrome staining. The expression levels of TGF-ß1 and downstream factors were determined by real-Time PCR, immunohistochemistry, and Western blot analysis. RESULTS Compared to Control rats, the CIH rats showed significant atrial interstitial fibrosis, longer inter-atrial conduction time, and elevated conduction inhomogeneity and AF inducibility, and the expression of TGF-ß1, TGF-ßRI, TGF-ßRII, P-Smad2/3, alpha-SMA, CTGF, and Collagen I were significantly increased, whereas the velocity of atrial conduction and the expression of miR-30c were dramatically decreased. All of these changes were significantly improved by Doxy treatment. CONCLUSIONS The findings suggested that Doxy can profoundly mitigate atrial fibrosis, conduction inhomogeneity as well as high AF inducibility secondary to fibrosis in a CIH rat model through suppressing the TGF-ß1 signaling pathway.


Assuntos
Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/fisiologia , Doxiciclina/farmacologia , Animais , Remodelamento Atrial/efeitos dos fármacos , China , Modelos Animais de Doenças , Doxiciclina/metabolismo , Fibrose/fisiopatologia , Átrios do Coração/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipóxia/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
14.
Biomed Pharmacother ; 124: 109854, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31981946

RESUMO

This review will cover the signalling pathways leading to the phosphorylation of the Smad linker region independent of Smad carboxy terminal phosphorylation. Characterising Smad linker region as a signalling pathway in its own right will encourage comprehensive signalling studies to provide solutions for successful discovery and exploitation of drug targets. The review describes Smad transcription factor signalling distinct from Transforming Growth Factor (TGF)-ß signalling. Novel signalling pathways represent new drug targets where these pathways are known to be involved in fibrosis, cancer and cardiovascular disease.


Assuntos
Fosforilação/fisiologia , Proteína Smad2/metabolismo , Animais , Doenças Cardiovasculares/fisiopatologia , Fibrose/fisiopatologia , Humanos , Neoplasias/fisiopatologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo
15.
Circ Res ; 126(4): 417-435, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31805819

RESUMO

RATIONALE: Trimeric intracellular cation (TRIC)-A and B are distributed to endoplasmic reticulum/sarcoplasmic reticulum intracellular Ca2+ stores. The crystal structure of TRIC has been determined, confirming the homotrimeric structure of a potassium channel. While the pore architectures of TRIC-A and TRIC-B are conserved, the carboxyl-terminal tail (CTT) domains of TRIC-A and TRIC-B are different from each other. Aside from its recognized role as a counterion channel that participates in excitation-contraction coupling of striated muscles, the physiological function of TRIC-A in heart physiology and disease has remained largely unexplored. OBJECTIVE: In cardiomyocytes, spontaneous Ca2+ waves, triggered by store overload-induced Ca2+ release mediated by the RyR2 (type 2 ryanodine receptor), develop extrasystolic contractions often associated with arrhythmic events. Here, we test the hypothesis that TRIC-A is a physiological component of RyR2-mediated Ca2+ release machinery that directly modulates store overload-induced Ca2+ release activity via CTT. METHODS AND RESULTS: We show that cardiomyocytes derived from the TRIC-A-/- (TRIC-A knockout) mice display dysregulated Ca2+ movement across sarcoplasmic reticulum. Biochemical studies demonstrate a direct interaction between CTT-A and RyR2. Modeling and docking studies reveal potential sites on RyR2 that show differential interactions with CTT-A and CTT-B. In HEK293 (human embryonic kidney) cells with stable expression of RyR2, transient expression of TRIC-A, but not TRIC-B, leads to apparent suppression of spontaneous Ca2+ oscillations. Ca2+ measurements using the cytosolic indicator Fura-2 and the endoplasmic reticulum luminal store indicator D1ER suggest that TRIC-A enhances Ca2+ leak across the endoplasmic reticulum by directly targeting RyR2 to modulate store overload-induced Ca2+ release. Moreover, synthetic CTT-A peptide facilitates RyR2 activity in lipid bilayer reconstitution system, enhances Ca2+ sparks in permeabilized TRIC-A-/- cardiomyocytes, and induces intracellular Ca2+ release after microinjection into isolated cardiomyocytes, whereas such effects were not observed with the CTT-B peptide. In response to isoproterenol stimulation, the TRIC-A-/- mice display irregular ECG and develop more fibrosis than the WT (wild type) littermates. CONCLUSIONS: In addition to the ion-conducting function, TRIC-A functions as an accessory protein of RyR2 to modulate sarcoplasmic reticulum Ca2+ handling in cardiac muscle.


Assuntos
Cálcio/metabolismo , Canais Iônicos/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Sinalização do Cálcio , Cardiotônicos/farmacologia , Eletrocardiografia/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Fibrose/genética , Fibrose/fisiopatologia , Células HEK293 , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Canais Iônicos/química , Canais Iônicos/genética , Isoproterenol/farmacologia , Camundongos Knockout , Simulação de Acoplamento Molecular , Miocárdio/citologia , Ligação Proteica , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo
16.
Life Sci ; 241: 117109, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31786195

RESUMO

AIMS: This study aimed to identify interstitial molecules that were responsible for the deterioration of the esiantimated glomerular filtration rate (eGFR) in diabetic nephropathy (DN). MATERIALS AND METHODS: Weighted gene co-expression network analysis (WGCNA) was used to link the tubulointerstitial gene expression profile of DN to eGFR values. The relationship of eGFR with each sub-domain regulator in the network was analyzed with the linear regression model. Gene sets enrichment analysis (GSEA) was applied to detect the molecular changes mostly relating to the essential regulators. KEY FINDINGS: Four co-expression modules were found strongly correlating with eGFR values. Genes from these modules were over-represented in fibrosis-related biological processes (extracellular matrix (ECM) organization and cell adhesion) and pathways (integrin signaling and ECM-receptor interaction). Of sub-domains in the gene interaction network, the expression of hypoxia-inducible factor 1A (HIF1A) was most negatively correlated with eGFR (R2 = 0.417, P = 0.026). The positive correlations between HIF1A and its target genes were found, indicating an enhanced transcriptional activity of HIF1A. We also found that HIF1A positively correlated with CCAAT enhancer binding protein delta (CEBPD) (r = 0.731, P = 0.011), an activator of HIF1A transcription. Moreover, GSEA showed that samples with high HIF1A expression were enriched with fibrosis associated signaling, like ECM-receptor interaction and cell adhesion. Intriguingly, vascular epithelial growth factor A (VEGFA) expression decreased while HIF1A increased (R2 = 0.733, P = 0.001), suggesting VEGFA loss may exacerbate hypoxia and stimulate HIF1A induction. SIGNIFICANCE: The present study suggested that interstitial HIF1A may be involved in renal interstitial fibrosis in DN.


Assuntos
Nefropatias Diabéticas/genética , Fibrose/fisiopatologia , Taxa de Filtração Glomerular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Rim/patologia , Adulto , Idoso , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/fisiopatologia , Feminino , Fibrose/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Taxa de Filtração Glomerular/fisiologia , Humanos , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/genética
17.
EuroIntervention ; 15(16): 1417-1423, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31532394

RESUMO

AIMS: We sought to investigate the relevance of myocardial fibrosis, assessed by mid-wall fibrosis risk (MFR) score, with respect to left ventricular (LV) reverse remodelling following transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: Between January 2010 and March 2015, we enrolled 207 patients in whom baseline MFR, which includes age, sex, high-sensitivity cardiac troponin I, presence of strain pattern on electrocardiography, and peak aortic valve velocity, as well as one-year follow-up echocardiography was available. LV reverse remodelling was defined as a >10% reduction in LV end-diastolic volume index (LVEDVi). A higher MFR score (≥52) was associated with increased LVEDVi and with decreased LV ejection fraction as well as higher baseline NT-proBNP levels (p<0.05 for all). One year after the TAVR procedure, a higher MFR score was associated with a decreased probability of LV reverse remodelling (OR 0.33, 95% CI: 0.23-0.87; p=0.03), which was independent of baseline echocardiographic parameters and comorbidities. In contrast, there was no significant difference in five-year mortality between patients with lower and higher MFR scores (57.9% vs 60.5%, p=0.66). CONCLUSIONS: A higher MFR score is associated with reduced LV reverse remodelling at one-year follow-up, whereas the MFR score does not appear to correlate with long-term mortality after TAVR.


Assuntos
Estenose da Valva Aórtica/cirurgia , Fibrose/fisiopatologia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Valva Aórtica , Humanos , Índice de Gravidade de Doença , Substituição da Valva Aórtica Transcateter/mortalidade , Resultado do Tratamento , Função Ventricular Esquerda
18.
Nephrol Dial Transplant ; 35(6): 964-970, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30418615

RESUMO

BACKGROUND: Although chronic hypoxia and fibrosis may be a key to the progression of chronic kidney disease (CKD), a noninvasive means of measuring these variables is not yet available. Here, using blood oxygen level-dependent (BOLD) and diffusion-weighted (DW) magnetic resonance imaging (MRI), we assessed changes in renal tissue oxygenation and fibrosis, respectively, and evaluated their correlation with prognosis for renal function. METHODS: The study was conducted under a single-center, longitudinal, retrospective observational design. We examined the prognostic significance of T2* values of BOLD-MRI and apparent diffusion coefficient (ADC) values on DW-MRI and other clinical parameters. The rate of decline in estimated glomerular filtration rate (eGFR) was calculated by linear regression analysis using changes in eGFR during the observation period. RESULTS: A total of 91 patients were enrolled, with a mean age of 55.8 ± 15.6 years. Among patients, 51 (56.0%) were males and 38 (41.8%) had diabetes mellitus. The mean eGFR was 49.2 ± 28.9 mL/min/1.73 m2 and the mean observation period was 5.13 years. ADC values of DW-MRI but not T2* values of BOLD-MRI were well correlated with eGFR at the initial time point. The mean annual rate of decline in eGFR during the 5-year observation period was -1.92 ± 3.00 mL/min/1.73 m2. On multiple linear regression analysis, the rate of decline in eGFR was significantly correlated with eGFR at the start point, period average amount of proteinuria and T2* values, but not with ADC values (t = 2.980, P = 0.004). CONCLUSIONS: Reduced oxygenation as determined by low T2* values on BOLD-MRI is a clinically useful marker of CKD progression.


Assuntos
Fibrose/fisiopatologia , Hipóxia/fisiopatologia , Imagem por Ressonância Magnética/métodos , Insuficiência Renal Crônica/patologia , Algoritmos , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
Arch Environ Occup Health ; 75(3): 152-158, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31107177

RESUMO

Clinical teaching generally asserts that large opacities of progressive massive fibrosis (PMF) on chest radiographs present primarily bilaterally in the upper lung zones, and with an elevated background profusion of small opacities. However, the contemporary basis for these descriptions is limited.Radiographs taken for the Coal Workers' Health Surveillance Program during 2000-2015 and previously determined to have large opacities ("PMF radiographs", n = 204), and a random sample previously deemed free of large opacities (n =22), were independently reevaluated by three National Institute for Occupational Safety and Health (NIOSH) B Readers. Large opacities were noted primarily in the upper right (41%) or upper left (28%) lung zone, but 31% were in middle or lower zones. Unilateral involvement was observed in 34% of readings, with right lung predominance (82%). The median small opacity profusion category for the radiographs with PMF was 2/1. The number of large opacities was not correlated with small opacity profusion category. The "classic" descriptions of PMF as bilateral, associated with elevated background profusions of small pneumoconiotic opacities, were each absent in a third of miners.


Assuntos
Minas de Carvão , Fibrose/diagnóstico por imagem , Fibrose/fisiopatologia , Doenças Profissionais , Radiografia Torácica , Progressão da Doença , Humanos , Saúde do Trabalhador , Pneumoconiose/epidemiologia , Pneumoconiose/fisiopatologia , Vigilância da População
20.
Jpn J Ophthalmol ; 64(1): 86-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31848785

RESUMO

PURPOSE: Congenital fibrosis of the extraocular muscles (CFEOM) is a rare nonprogressive disorder characterized by bilateral ptosis, with severely limited ocular motility. We report the treatment outcomes and problems in 3 cases of pediatric CFEOM in which extraocular muscle surgery was performed. CASES: All the cases showed bilateral ptosis and a chin-up abnormal head posture (AHP). Case 1 A 6-year-old girl. Both eyes were fixed downward with esotropia and could not elevate above the horizontal midline. She underwent simultaneous bilateral inferior rectus (IR) and medial rectus (MR) recession. Postoperatively, 8-prism-diopter (PD) exotropia was observed, and the AHP were improved, but MR advancement in the right eye was necessary because A-pattern exotropia became prominent starting about 10 months postoperatively. Case 2 A 7-year-old girl. Both eyes were fixed downward and did not elevate over the midline. She underwent bilateral IR recession. Postoperatively, 8-PD exotropia was observed; however, A-pattern exotropia became prominent gradually at about 1 year and 7 months postoperatively, and bilateral lateral rectus (LR) recession was added. Case 3 A 6-year-old girl. Both eyes were fixed downward but could be elevated above the horizontal midline by upward effort. She underwent bilateral IR recession, which resulted in improvement of the AHP and ptosis. About 8 months postoperatively, exotropia was evident only in the downward gaze. CONCLUSIONS: Bilateral IR recession in pediatric patients with CFEOM was effective in improving AHP, but postoperative exotropia appeared to be inevitable owing to the diminished adducted function caused by IR recession. Thus, horizontal strabismus surgery should be planned after the results of IR recession become evident.


Assuntos
Fibrose/cirurgia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos , Oftalmoplegia/cirurgia , Criança , Movimentos Oculares/fisiologia , Feminino , Fibrose/diagnóstico por imagem , Fibrose/fisiopatologia , Cabeça/fisiologia , Humanos , Músculos Oculomotores/fisiopatologia , Oftalmoplegia/diagnóstico por imagem , Oftalmoplegia/fisiopatologia , Postura , Tomografia Computadorizada por Raios X , Visão Binocular/fisiologia
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