scholarly journals Fibroblast Activation Protein Targeted Photodynamic Therapy Selectively Kills Activated Skin Fibroblasts from Systemic Sclerosis Patients and Prevents Tissue Contraction

2021 ◽  
Vol 22 (23) ◽  
pp. 12681
Author(s):  
Daphne N. Dorst ◽  
Arjan P. M. van Caam ◽  
Elly L. Vitters ◽  
Birgitte Walgreen ◽  
Monique M. A. Helsen ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Systemic Sclerosis ◽  
Light Exposure ◽  
Collagen Type I ◽  
Fibroblast Activation Protein ◽  
Skin Fibroblasts ◽  
Type I ◽  
Fibroblast Activation ◽  
Tissue Contraction ◽  
Targeted Photodynamic Therapy

Systemic sclerosis (SSc) is a rare, severe, auto-immune disease characterized by inflammation, vasculopathy and fibrosis. Activated (myo)fibroblasts are crucial drivers of this fibrosis. By exploiting their expression of fibroblast activation protein (FAP) to perform targeted photodynamic therapy (tPDT), we can locoregionally deplete these pathogenic cells. In this study, we explored the use of FAP-tPDT in primary skin fibroblasts from SSc patients, both in 2D and 3D cultures. Method: The FAP targeting antibody 28H1 was conjugated with the photosensitizer IRDye700DX. Primary skin fibroblasts were obtained from lesional skin biopsies of SSc patients via spontaneous outgrowth and subsequently cultured on plastic or collagen type I. For 2D FAP-tPDT, cells were incubated in buffer with or without the antibody-photosensitizer construct, washed after 4 h and exposed to λ = 689 nm light. Cell viability was measured using CellTiter Glo®®. For 3D FAP-tPDT, cells were seeded in collagen plugs and underwent the same treatment procedure. Contraction of the plugs was followed over time to determine myofibroblast activity. Results: FAP-tPDT resulted in antibody-dose dependent cytotoxicity in primary skin fibroblasts upon light exposure. Cells not exposed to light or incubated with an irrelevant antibody-photosensitizer construct did not show this response. FAP-tPDT fully prevented contraction of collagen plugs seeded with primary SSc fibroblasts. Even incubation with a very low dose of antibody (0.4 nM) inhibited contraction in 2 out of 3 donors. Conclusions: Here we have shown, for the first time, the potential of FAP-tPDT for the treatment of fibrosis in SSc skin.

scholarly journals Circulating fibroblast activation protein and dipeptidyl peptidase 4 in rheumatoid arthritis and systemic sclerosis

2016 ◽  
Vol 21 (11) ◽  
pp. 1915-1923 ◽  
Author(s):  
Premarani Sinnathurai ◽  
Wendy Lau ◽  
Ana Julia Vieira de Ribeiro ◽  
William W. Bachovchin ◽  
Helen Englert ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Sclerosis ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Dipeptidyl Peptidase 4 ◽  
Fibroblast Activation

Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment

2019 ◽  
Vol 105 (1) ◽  
pp. 106-115 ◽  
Author(s):  
Mai C Arlien-Søborg ◽  
Camilla Grøndahl ◽  
Amanda Bæk ◽  
Jakob Dal ◽  
Michael Madsen ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Disease Control ◽  
Fibroblast Activation Protein ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Type I ◽  
Collagen Turnover ◽  
Fibroblast Activation ◽  
Before And After ◽  
Turnover Markers

Abstract Background Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. Aim To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. Methods Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). Results Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). Conclusion 1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. Clinical Trials Registration NCT00647179

scholarly journals The Protective Effect of Rosmarinic Acid against Unfavorable Influence of Methylparaben and Propylparaben on Collagen in Human Skin Fibroblasts

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1282 ◽  
Author(s):  
Natalia Matwiejczuk ◽  
Anna Galicka ◽  
Ilona Zaręba ◽  
Małgorzata M. Brzóska
Keyword(s):  
Adverse Effects ◽  
Human Skin ◽  
Rosmarinic Acid ◽  
Harmful Effect ◽  
Collagen Type I ◽  
Skin Fibroblasts ◽  
Type I ◽  
Cosmetic Products ◽  
Human Skin Fibroblasts ◽  
Protein Levels

Parabens, which are widely used in food, medicines and cosmetics, have a harmful effect on human health. People are most exposed to parabens transdermally by using cosmetic products containing these preservatives. The purpose of this study was to estimate the influence of parabens (methylparaben—MP and propylparaben—PP) on the metabolism of collagen in the human skin fibroblasts and above all, to assess whether rosmarinic acid (RA—50, 100, or 150 μM) can protect these cells from the adverse effects of parabens (0.001% MP and 0.0003% PP, 0.003% MP and 0.001% PP, and 0.01% MP and 0.003% PP). The possible mechanisms of RA action were estimated as well. Parabens decreased the expression of collagen type I and III at mRNA and protein levels, while RA (depending on the concentration) provided partial or total protection against these changes. The effective protection against the adverse effects of parabens on cell viability and proliferation was also provided by RA. The beneficial impact of RA on collagen and the fibroblasts resulted from an independent action of this compound and its interaction with parabens. This study allows us to conclude that this polyphenolic compound may protect from unfavorable health outcomes caused by lifetime human exposure to parabens contained in cosmetic products.

scholarly journals Effect of Captopril and Melatonin on Fibrotic Rebuilding of the Aorta in 24 Hour Light-Induced Hypertension

2013 ◽  
pp. S135-S141 ◽  
Author(s):  
K. REPOVÁ-BEDNÁROVÁ ◽  
S. AZIRIOVÁ ◽  
J. HRENÁK ◽  
K. KRAJČÍROVIČOVÁ ◽  
M. ADAMCOVÁ ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Light Exposure ◽  
Continuous Light ◽  
Collagen Type I ◽  
Collagen I ◽  
Aortic Tissue ◽  
Type I ◽  
Collagen Iii ◽  
Induced Hypertension ◽  
Aortic Media

Chronic continuous light exposure leads to melatonin deficiency along with complex neurohumoral activation resulting in hypertension development in rats. The aim of this study was to show, whether continuous light induces fibrotic rebuilding of the aorta and whether the treatment with melatonin or angiotensin converting enzyme inhibitor captopril can prevent these potential alterations. In a six-week experiment, 3-month-old Wistar rats were divided into 4 groups (ten per group): controls, rats exposed to continuous light, exposed to continuous light plus treated with captopril (100 mg/kg/24 h) and exposed to continuous light plus treated with melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP) and collagen type I and III in the media of thoracic aorta were measured. Continuous light induced hypertension and fibrotic rebuilding of the aorta in terms of enhancement of collagen I and III concentration in the aortic media. Both captopril and melatonin prevented SBP rise and reduced collagen III concentration in the aorta. However, only melatonin reduced collagen I and the sum of collagen I and III in the aortic tissue. We conclude that in continuous light-induced hypertension, administration of melatonin, along with SBP reduction, decreases collagen I and III concentration in the aorta. It is suggested that antifibrotic effect of melatonin may reduce the stiffness of the aorta and small arteries and beneficially influence the nature of the pulse wave and peripheral vascular resistance.

P715Deletion of fibroblast activation protein decreases experimental atherosclerotic plaque formation and vulnerability

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Stein ◽  
J Weber ◽  
S Nusser-Stein ◽  
J Pahla ◽  
H Zhang ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Cross Sections ◽  
Aortic Root ◽  
Fibroblast Activation Protein ◽  
Plaque Formation ◽  
Type I ◽  
Plaque Vulnerability ◽  
Fibroblast Activation ◽  
Atherosclerotic Plaque Formation ◽  
Deficient Mice

Abstract Background Fibroblast activation protein (FAP) is a serine protease that is upregulated in sites of tissue remodeling, including arthritis, tumors and atherosclerosis. We have reported that FAP degrades type I collagen in human thin-cap fibroatheromata; its expression is enhanced in advanced human plaques and induced by inflammation. However, the role of endogenous FAP in atherosclerosis remains unknown. Purpose To investigate the effects of constitutive Fap loss-of-function on atherosclerotic plaque formation and vulnerability. Methods and results Male 8-week-old Apoe−/− Fap+/+ and Apoe−/− Fap−/− mice were fed a high-cholesterol diet (1.25% chol) for 12 weeks. En face analyses of thoracoabdominal aortae using Oil Red O (ORO) revealed decreased plaques in Apoe−/− Fap−/− mice (5.7±0.5%; n=21) compared to Apoe−/− Fap+/+ mice (10.7±0.7%; n=24; p<0.0001). In parallel, ORO analyses of serial aortic root cross sections showed diminished plaques in Fap-deficient mice (18.4±3.4% vs 27.6±2.1%). As a surrogate of plaque vulnerability, fibrous cap thickness was increased in Apoe−/− Fap−/− mice (65±6 mm vs 35±3 mm; p<0.01), whereas necrotic core size, plaque macrophages (CD68) and T cells (CD3) accumulation, as well as VCAM1 expression did not differ. These changes were independent of plasma triglycerides, total and LDL-cholesterol levels. Plasma of Fap-deficient mice showed decreased FAP activity compared to Fap wildtype controls. Notably, second harmonics generation in cross sections of aortic root plaques showed that the deposition and density of fibrillar collagens was enhanced in Fap-deficient (25.5±4.4%) compared to control plaques (13.8±2.5%; p<0.05). Consistently, Fap deletion led to an accumulation of uncleaved pre-COL3A1, a proteolytic target of FAP. Conclusions Constitutive Fap deletion decreases experimental atherosclerosis and features of plaque vulnerability. Thus, inhibition of FAP expression or activity may be a promising therapeutic target in atherosclerosis. Acknowledgement/Funding Swiss National Science Foundation, Swiss Heart Foundation

scholarly journals SAT0301 CIRCULATING FIBROCYTES FROM SYSTEMIC SCLEROSIS PATIENTS AS POSSIBLE TARGET OF CTLA4-IG TREATMENT: AN IN VITRO STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1096.1-1096
Author(s):  
S. Soldano ◽  
P. Montagna ◽  
S. Paolino ◽  
E. Alessandri ◽  
C. Pizzorni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Costimulatory Molecule ◽  
Skin Fibroblasts ◽  
Type I ◽  
Research Support ◽  
Hla Dr ◽  
Antigen Presenting ◽  
Circulating Fibrocytes

Background:muscle actin (aSMA)+cells involved in the overproduction of extracellular matrix proteins, primarily fibronectin (FN) and type I collagen (COL1) at the level of damaged tissues (1). These cells may originate from different cell types including fibroblasts, endothelial and epithelial cells, and fibrocytes (1). Circulating fibrocytes are bone marrow progenitor cells expressing specific markers of hematopoietic (CD34, CD45, and MHC class II) and stromal cells (COL1 and COL3), chemokine receptors (CCR2, CCR7), and CXCR4 (2). CXCR4 regulates fibrocyte migration into injured tissues allowing their differentiation into fibroblasts/myofibroblasts (2).In vitro, fibrocytes differentiate from circulating CD14+monocytes showing an antigen-presenting capability through the expression of HLA-DR and costimulatory molecule CD86 (2). CTLA4-Ig fusion protein (abatacept) interacts with CD86 on cell surface of antigen presenting cells (APCs), such as macrophages and endothelial cells (3,4).Objectives:To investigate the possible effect of CTLA4-Ig treatment on cultured human fibrocytes and skin fibroblasts isolated from the same systemic sclerosis patients (SSc pts).Methods:Fibrocytes isolated from the peripheral blood mononuclear cells of SSc pts and healthy subjects (HSs) were cultured on fibronectin-coated plates in DMEM at 20% of FBS; for further 8 days (T8) to allow their complete differentiation. Differentiated fibrocytes were maintained in growth medium or treated with CTLA4-Ig at different concentrations (10, 50, 100, and 500μg/ml) for 3 hours. Fibroblasts were isolated from the skin biopsies of the same patients and HSs, cultured until the 3rdpassage in RPMI at 10% FBS and then treated with CTLA4-Ig for 24 and 48 hours. Fibrocytes were characterized as CD45+CXCR4+COL1+cells and the expression of CD86 and HLA-DR was also evaluated. The gene expression of aSMA, COL1, CXCR4, TGFb1 and CD86 was investigated by quantitative real-time polymerase chain reaction in cultured fibrocytes and skin fibroblasts. In cultured skin fibroblasts, COL1 and fibronectin synthesis was evaluated by Western blotting.Results:Treatment with CTLA4-Ig for 3 hours significantly downregulated aSMA and COL1 gene expression in cultured SSc fibrocytes at T8 (p<0.01, p<0.05 vs. untreated fibrocytes), whereas no modulatory effect was observed on the TGFbeta1 and CXCR4 gene expression. In cultured SSc skin fibroblasts, CTLA4-Ig did not induce any significant effect on CD68, TGFb1, COL1 and FN gene expression as well as COL1 and FN protein synthesis, both after 24 and 48 hours. Of note, these cultured SSc skin fibroblasts showed a low expression of CD86.Conclusion:Due to their high expression of CD86, circulating fibrocytes seem to be more responsive to CTLA4-Ig treatment than the skin fibroblasts isolated from the same SSc patient.References:[1]Cutolo M et al. Expert Rev Clin Immunol. 2019;15:753-64.[2]Bucala R. Mol Med.2015;2:S3-5.[3]Cutolo M et al. Clin Exp Rheumatol. 2015;33:250-4.[4]Brizzolara R et al. J Rheumatol. 2013;40:738-40.Disclosure of Interests:Stefano Soldano: None declared, Paola Montagna: None declared, Sabrina Paolino: None declared, Elisa Alessandri: None declared, Carmen Pizzorni: None declared, Greta Pacini: None declared, Federica Goegan: None declared, Alberto Sulli Grant/research support from: Laboratori Baldacci, Carlotta Schenone: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha

scholarly journals Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate

Rheumatology ◽  
2010 ◽  
Vol 49 (11) ◽  
pp. 2024-2036 ◽  
Author(s):  
A. Dooley ◽  
X. Shi-Wen ◽  
N. Aden ◽  
T. Tranah ◽  
N. Desai ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Collagen Type ◽  
Dermal Fibroblast ◽  
Collagen Type I ◽  
Type I
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