The Experts below are selected from a list of 11376 Experts worldwide ranked by ideXlab platform
Peter Caravan - One of the best experts on this subject based on the ideXlab platform.
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improving the reactivity of hydrazine bearing mri probes for in vivo imaging of lung Fibrogenesis
Chemical Science, 2020Co-Authors: Eman A Akam, Nicholas J Rotile, Eric Abston, Hannah Slattery, I Y Zhou, Michael Lanuti, Peter CaravanAbstract:Pulmonary fibrosis (PF) is the pathologic accumulation of extracellular matrix components in lung tissue that result in scarring following chronic lung injury. PF is typically diagnosed by high resolution computed tomography (HRCT) and/or invasive biopsy. However, HRCT cannot distinguish old injury from active Fibrogenesis. We previously demonstrated that allysine residues on oxidized collagen represent an abundant target during lung Fibrogenesis, and that magnetic resonance imaging (MRI) with a small-molecule, gadolinium-containing probe, Gd-Hyd, could specifically detect and stage Fibrogenesis in a mouse model. In this work, we present an improved probe, Gd-CHyd, featuring an N,N-dialkyl hydrazine which has an order of magnitude both greater reactivity and affinity for aldehydes. In a paired study in mice with bleomycin induced lung injury we show that the improved reactivity and affinity of Gd-CHyd results in significantly higher lung-to-liver contrast, e.g. 77% higher at 45 min post injection, and slower lung clearance than Gd-Hyd. Gd-CHyd enhanced MRI is >60-fold higher in bleomycin injured mouse lungs compared to uninjured mice. Collectively, our data indicate that enhancing hydrazine reactivity and affinity towards allysine is an effective strategy to significantly improve molecular MRI probes for lung Fibrogenesis.
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68ga nodaga indole an allysine reactive positron emission tomography probe for molecular imaging of pulmonary Fibrogenesis
Journal of the American Chemical Society, 2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Michael Lanuti, Junfeng Wang, Jingyi Sui, Bryan C. Fuchs, Pauline Desogere, Katherine A Grahamoregan, Peter CaravanAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, all...
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Molecular Probes for Imaging Fibrosis and Fibrogenesis
Chemistry (Weinheim an der Bergstrasse Germany), 2018Co-Authors: Pauline Desogere, Sydney B. Montesi, Peter CaravanAbstract:Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common result of chronic tissue injury. Advances in the clinical management of fibrotic diseases have been hampered by the low sensitivity and specificity of noninvasive early diagnostic options, lack of surrogate end points for use in clinical trials, and a paucity of noninvasive tools to assess fibrotic disease activity longitudinally. Hence, the development of new methods to image fibrosis and Fibrogenesis is a large unmet clinical need. Herein, an overview of recent and selected molecular probes for imaging of fibrosis and Fibrogenesis by magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography is provided.
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68ga nodaga indole an allysine reactive pet probe for molecular imaging of actively progressive pulmonary Fibrogenesis
The Journal of Nuclear Medicine, 2018Co-Authors: Jessica Wahsner, Nicholas J Rotile, Michael Lanuti, Junfeng Wang, Bryan C. Fuchs, Pauline Desogere, Derek J Erstad, Peter CaravanAbstract:260 Objectives: Tissue fibrosis is the accumulation of extracellular matrix molecules that make up scar tissue as a consequence of chronic tissue injury and accounts for nearly half of the deaths in the industrialized world.1 There is an unmet need to develop effective methods for noninvasive detection of actively progressive Fibrogenesis. Noninvasive methods that can distinguish active Fibrogenesis from stable scar tissue provide indispensable insights for monitoring disease activity or therapeutic responses.Allysine-rich collagen, which promotes its crosslinking is a marker of active Fibrogenesis.2,3 Here, we report a novel 68Ga-NODAGA based PET probe that targets allysine residues in active pulmonary Fibrogenesis. Methods: The allysine-reactive PET probe 68Ga-NODAGA-indole was synthesized by conjugation of a macrocyclic chelator (NODAGA) to a functionalized indole that rapidly forms hydrolytically stable condensation products with aldehydes at physiological pH, followed by labeling with 68Ga. The non-reactive analogue 68Ga-NODAGA-carboline was also synthesized, incapable of undergoing condensation reactions with aldehydes. Both probes were evaluated in the bleomycin mouse (BM) model of pulmonary fibrosis and in healthy animals. In vivo studies include biodistribution and small animal PET-CT imaging after intravenous injection of the active probe 14 days after bleomycin whereas the inactive probe was injected 13 days after bleomycin. Additionally, characterization of collagen/ allysine content and histology was performed. Pharmacokinetics of the probes were evaluated in healthy mice. Results: The active probe, 68Ga-NODAGA-indole, and the control probe, 68Ga-NODAGA-carboline, showed similar low, nonspecific uptake in the lungs of control mice. In the well-established bleomycin mouse model of pulmonary fibrosis, active probe 68Ga-NODAGA-indole showed 3-fold increased uptake in fibrotic lungs relative to the control probe, 68Ga-NODAGA-carboline, applied in the same disease model. The control probe, 68Ga-NODAGA-carboline, showed similar uptake in the lungs of both fibrotic and control mice. Conclusion: We demonstrated that a small molecule PET probe can be applied for the molecular imaging of active Fibrogenesis. Research Support: This project is supported by the National Institutes of Health (EB009062, HL131907, RR029495). JW is supported by the German Research Foundation (DFG). References: 1. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med.2013, 5:167sr161. 2. Chen HH, Waghorn PA, Wei L, Tapias LF, Schu Hle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic Fibrogenesis JCI Insight.2017, 2. 3. Waghorn PA, Jones CM, Rotile NJ, Koerner SK, Ferreira DS, Chen HH, Probst CK, Tager AM, Caravan P. Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe Angew Chem Int Ed Engl.2017, 56:9825-9828.
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molecular magnetic resonance imaging of lung Fibrogenesis with an oxyamine based probe
Angewandte Chemie, 2017Co-Authors: Philip A Waghorn, Chloe M Jones, Nicholas J Rotile, Steffi K Koerner, Diego Dos Santos Ferreira, Howard H Chen, Clemens K Probst, Andrew M Tager, Peter CaravanAbstract:Fibrogenesis is the active production of extracellular matrix in response to tissue injury. In many chronic diseases persistent Fibrogenesis results in the accumulation of scar tissue, which can lead to organ failure and death. However, no non-invasive technique exists to assess this key biological process. All tissue Fibrogenesis results in the formation of allysine, which enables collagen cross-linking and leads to tissue stiffening and scar formation. We report herein a novel allysine-binding gadolinium chelate (GdOA), that can non-invasively detect and quantify the extent of Fibrogenesis using magnetic resonance imaging (MRI). We demonstrate that GdOA signal enhancement correlates with the extent of the disease and is sensitive to a therapeutic response.
Jessica Wahsner - One of the best experts on this subject based on the ideXlab platform.
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68ga nodaga indole an allysine reactive positron emission tomography probe for molecular imaging of pulmonary Fibrogenesis
Journal of the American Chemical Society, 2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Michael Lanuti, Junfeng Wang, Jingyi Sui, Bryan C. Fuchs, Pauline Desogere, Katherine A Grahamoregan, Peter CaravanAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, all...
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68Ga-NODAGA-Indole: An Allysine-Reactive Positron Emission Tomography Probe for Molecular Imaging of Pulmonary Fibrogenesis
2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Pauline Désogère, Katherine A. Graham-o’regan, Junfeng Wang, Markus D. Schirmer, Diêgo Dos Santos Ferreira, Jingyi Sui, Bryan C. FuchsAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, allysine-binding positron emission tomography probe, 68Ga-NODAGA-indole, that can noninvasively detect and quantify pulmonary Fibrogenesis. We demonstrate that the uptake of 68Ga-NODAGA-indole in actively fibrotic lungs is 7-fold higher than in control groups and that uptake is linearly correlated (R2 = 0.98) with the concentration of lung allysine
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68ga nodaga indole an allysine reactive pet probe for molecular imaging of actively progressive pulmonary Fibrogenesis
The Journal of Nuclear Medicine, 2018Co-Authors: Jessica Wahsner, Nicholas J Rotile, Michael Lanuti, Junfeng Wang, Bryan C. Fuchs, Pauline Desogere, Derek J Erstad, Peter CaravanAbstract:260 Objectives: Tissue fibrosis is the accumulation of extracellular matrix molecules that make up scar tissue as a consequence of chronic tissue injury and accounts for nearly half of the deaths in the industrialized world.1 There is an unmet need to develop effective methods for noninvasive detection of actively progressive Fibrogenesis. Noninvasive methods that can distinguish active Fibrogenesis from stable scar tissue provide indispensable insights for monitoring disease activity or therapeutic responses.Allysine-rich collagen, which promotes its crosslinking is a marker of active Fibrogenesis.2,3 Here, we report a novel 68Ga-NODAGA based PET probe that targets allysine residues in active pulmonary Fibrogenesis. Methods: The allysine-reactive PET probe 68Ga-NODAGA-indole was synthesized by conjugation of a macrocyclic chelator (NODAGA) to a functionalized indole that rapidly forms hydrolytically stable condensation products with aldehydes at physiological pH, followed by labeling with 68Ga. The non-reactive analogue 68Ga-NODAGA-carboline was also synthesized, incapable of undergoing condensation reactions with aldehydes. Both probes were evaluated in the bleomycin mouse (BM) model of pulmonary fibrosis and in healthy animals. In vivo studies include biodistribution and small animal PET-CT imaging after intravenous injection of the active probe 14 days after bleomycin whereas the inactive probe was injected 13 days after bleomycin. Additionally, characterization of collagen/ allysine content and histology was performed. Pharmacokinetics of the probes were evaluated in healthy mice. Results: The active probe, 68Ga-NODAGA-indole, and the control probe, 68Ga-NODAGA-carboline, showed similar low, nonspecific uptake in the lungs of control mice. In the well-established bleomycin mouse model of pulmonary fibrosis, active probe 68Ga-NODAGA-indole showed 3-fold increased uptake in fibrotic lungs relative to the control probe, 68Ga-NODAGA-carboline, applied in the same disease model. The control probe, 68Ga-NODAGA-carboline, showed similar uptake in the lungs of both fibrotic and control mice. Conclusion: We demonstrated that a small molecule PET probe can be applied for the molecular imaging of active Fibrogenesis. Research Support: This project is supported by the National Institutes of Health (EB009062, HL131907, RR029495). JW is supported by the German Research Foundation (DFG). References: 1. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med.2013, 5:167sr161. 2. Chen HH, Waghorn PA, Wei L, Tapias LF, Schu Hle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic Fibrogenesis JCI Insight.2017, 2. 3. Waghorn PA, Jones CM, Rotile NJ, Koerner SK, Ferreira DS, Chen HH, Probst CK, Tager AM, Caravan P. Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe Angew Chem Int Ed Engl.2017, 56:9825-9828.
Nicholas J Rotile - One of the best experts on this subject based on the ideXlab platform.
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improving the reactivity of hydrazine bearing mri probes for in vivo imaging of lung Fibrogenesis
Chemical Science, 2020Co-Authors: Eman A Akam, Nicholas J Rotile, Eric Abston, Hannah Slattery, I Y Zhou, Michael Lanuti, Peter CaravanAbstract:Pulmonary fibrosis (PF) is the pathologic accumulation of extracellular matrix components in lung tissue that result in scarring following chronic lung injury. PF is typically diagnosed by high resolution computed tomography (HRCT) and/or invasive biopsy. However, HRCT cannot distinguish old injury from active Fibrogenesis. We previously demonstrated that allysine residues on oxidized collagen represent an abundant target during lung Fibrogenesis, and that magnetic resonance imaging (MRI) with a small-molecule, gadolinium-containing probe, Gd-Hyd, could specifically detect and stage Fibrogenesis in a mouse model. In this work, we present an improved probe, Gd-CHyd, featuring an N,N-dialkyl hydrazine which has an order of magnitude both greater reactivity and affinity for aldehydes. In a paired study in mice with bleomycin induced lung injury we show that the improved reactivity and affinity of Gd-CHyd results in significantly higher lung-to-liver contrast, e.g. 77% higher at 45 min post injection, and slower lung clearance than Gd-Hyd. Gd-CHyd enhanced MRI is >60-fold higher in bleomycin injured mouse lungs compared to uninjured mice. Collectively, our data indicate that enhancing hydrazine reactivity and affinity towards allysine is an effective strategy to significantly improve molecular MRI probes for lung Fibrogenesis.
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68ga nodaga indole an allysine reactive positron emission tomography probe for molecular imaging of pulmonary Fibrogenesis
Journal of the American Chemical Society, 2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Michael Lanuti, Junfeng Wang, Jingyi Sui, Bryan C. Fuchs, Pauline Desogere, Katherine A Grahamoregan, Peter CaravanAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, all...
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68Ga-NODAGA-Indole: An Allysine-Reactive Positron Emission Tomography Probe for Molecular Imaging of Pulmonary Fibrogenesis
2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Pauline Désogère, Katherine A. Graham-o’regan, Junfeng Wang, Markus D. Schirmer, Diêgo Dos Santos Ferreira, Jingyi Sui, Bryan C. FuchsAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, allysine-binding positron emission tomography probe, 68Ga-NODAGA-indole, that can noninvasively detect and quantify pulmonary Fibrogenesis. We demonstrate that the uptake of 68Ga-NODAGA-indole in actively fibrotic lungs is 7-fold higher than in control groups and that uptake is linearly correlated (R2 = 0.98) with the concentration of lung allysine
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68ga nodaga indole an allysine reactive pet probe for molecular imaging of actively progressive pulmonary Fibrogenesis
The Journal of Nuclear Medicine, 2018Co-Authors: Jessica Wahsner, Nicholas J Rotile, Michael Lanuti, Junfeng Wang, Bryan C. Fuchs, Pauline Desogere, Derek J Erstad, Peter CaravanAbstract:260 Objectives: Tissue fibrosis is the accumulation of extracellular matrix molecules that make up scar tissue as a consequence of chronic tissue injury and accounts for nearly half of the deaths in the industrialized world.1 There is an unmet need to develop effective methods for noninvasive detection of actively progressive Fibrogenesis. Noninvasive methods that can distinguish active Fibrogenesis from stable scar tissue provide indispensable insights for monitoring disease activity or therapeutic responses.Allysine-rich collagen, which promotes its crosslinking is a marker of active Fibrogenesis.2,3 Here, we report a novel 68Ga-NODAGA based PET probe that targets allysine residues in active pulmonary Fibrogenesis. Methods: The allysine-reactive PET probe 68Ga-NODAGA-indole was synthesized by conjugation of a macrocyclic chelator (NODAGA) to a functionalized indole that rapidly forms hydrolytically stable condensation products with aldehydes at physiological pH, followed by labeling with 68Ga. The non-reactive analogue 68Ga-NODAGA-carboline was also synthesized, incapable of undergoing condensation reactions with aldehydes. Both probes were evaluated in the bleomycin mouse (BM) model of pulmonary fibrosis and in healthy animals. In vivo studies include biodistribution and small animal PET-CT imaging after intravenous injection of the active probe 14 days after bleomycin whereas the inactive probe was injected 13 days after bleomycin. Additionally, characterization of collagen/ allysine content and histology was performed. Pharmacokinetics of the probes were evaluated in healthy mice. Results: The active probe, 68Ga-NODAGA-indole, and the control probe, 68Ga-NODAGA-carboline, showed similar low, nonspecific uptake in the lungs of control mice. In the well-established bleomycin mouse model of pulmonary fibrosis, active probe 68Ga-NODAGA-indole showed 3-fold increased uptake in fibrotic lungs relative to the control probe, 68Ga-NODAGA-carboline, applied in the same disease model. The control probe, 68Ga-NODAGA-carboline, showed similar uptake in the lungs of both fibrotic and control mice. Conclusion: We demonstrated that a small molecule PET probe can be applied for the molecular imaging of active Fibrogenesis. Research Support: This project is supported by the National Institutes of Health (EB009062, HL131907, RR029495). JW is supported by the German Research Foundation (DFG). References: 1. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med.2013, 5:167sr161. 2. Chen HH, Waghorn PA, Wei L, Tapias LF, Schu Hle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic Fibrogenesis JCI Insight.2017, 2. 3. Waghorn PA, Jones CM, Rotile NJ, Koerner SK, Ferreira DS, Chen HH, Probst CK, Tager AM, Caravan P. Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe Angew Chem Int Ed Engl.2017, 56:9825-9828.
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molecular magnetic resonance imaging of lung Fibrogenesis with an oxyamine based probe
Angewandte Chemie, 2017Co-Authors: Philip A Waghorn, Chloe M Jones, Nicholas J Rotile, Steffi K Koerner, Diego Dos Santos Ferreira, Howard H Chen, Clemens K Probst, Andrew M Tager, Peter CaravanAbstract:Fibrogenesis is the active production of extracellular matrix in response to tissue injury. In many chronic diseases persistent Fibrogenesis results in the accumulation of scar tissue, which can lead to organ failure and death. However, no non-invasive technique exists to assess this key biological process. All tissue Fibrogenesis results in the formation of allysine, which enables collagen cross-linking and leads to tissue stiffening and scar formation. We report herein a novel allysine-binding gadolinium chelate (GdOA), that can non-invasively detect and quantify the extent of Fibrogenesis using magnetic resonance imaging (MRI). We demonstrate that GdOA signal enhancement correlates with the extent of the disease and is sensitive to a therapeutic response.
Bryan C. Fuchs - One of the best experts on this subject based on the ideXlab platform.
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68ga nodaga indole an allysine reactive positron emission tomography probe for molecular imaging of pulmonary Fibrogenesis
Journal of the American Chemical Society, 2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Michael Lanuti, Junfeng Wang, Jingyi Sui, Bryan C. Fuchs, Pauline Desogere, Katherine A Grahamoregan, Peter CaravanAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, all...
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68Ga-NODAGA-Indole: An Allysine-Reactive Positron Emission Tomography Probe for Molecular Imaging of Pulmonary Fibrogenesis
2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Pauline Désogère, Katherine A. Graham-o’regan, Junfeng Wang, Markus D. Schirmer, Diêgo Dos Santos Ferreira, Jingyi Sui, Bryan C. FuchsAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde allysine, is a universal feature of Fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, allysine-binding positron emission tomography probe, 68Ga-NODAGA-indole, that can noninvasively detect and quantify pulmonary Fibrogenesis. We demonstrate that the uptake of 68Ga-NODAGA-indole in actively fibrotic lungs is 7-fold higher than in control groups and that uptake is linearly correlated (R2 = 0.98) with the concentration of lung allysine
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68ga nodaga indole an allysine reactive pet probe for molecular imaging of actively progressive pulmonary Fibrogenesis
The Journal of Nuclear Medicine, 2018Co-Authors: Jessica Wahsner, Nicholas J Rotile, Michael Lanuti, Junfeng Wang, Bryan C. Fuchs, Pauline Desogere, Derek J Erstad, Peter CaravanAbstract:260 Objectives: Tissue fibrosis is the accumulation of extracellular matrix molecules that make up scar tissue as a consequence of chronic tissue injury and accounts for nearly half of the deaths in the industrialized world.1 There is an unmet need to develop effective methods for noninvasive detection of actively progressive Fibrogenesis. Noninvasive methods that can distinguish active Fibrogenesis from stable scar tissue provide indispensable insights for monitoring disease activity or therapeutic responses.Allysine-rich collagen, which promotes its crosslinking is a marker of active Fibrogenesis.2,3 Here, we report a novel 68Ga-NODAGA based PET probe that targets allysine residues in active pulmonary Fibrogenesis. Methods: The allysine-reactive PET probe 68Ga-NODAGA-indole was synthesized by conjugation of a macrocyclic chelator (NODAGA) to a functionalized indole that rapidly forms hydrolytically stable condensation products with aldehydes at physiological pH, followed by labeling with 68Ga. The non-reactive analogue 68Ga-NODAGA-carboline was also synthesized, incapable of undergoing condensation reactions with aldehydes. Both probes were evaluated in the bleomycin mouse (BM) model of pulmonary fibrosis and in healthy animals. In vivo studies include biodistribution and small animal PET-CT imaging after intravenous injection of the active probe 14 days after bleomycin whereas the inactive probe was injected 13 days after bleomycin. Additionally, characterization of collagen/ allysine content and histology was performed. Pharmacokinetics of the probes were evaluated in healthy mice. Results: The active probe, 68Ga-NODAGA-indole, and the control probe, 68Ga-NODAGA-carboline, showed similar low, nonspecific uptake in the lungs of control mice. In the well-established bleomycin mouse model of pulmonary fibrosis, active probe 68Ga-NODAGA-indole showed 3-fold increased uptake in fibrotic lungs relative to the control probe, 68Ga-NODAGA-carboline, applied in the same disease model. The control probe, 68Ga-NODAGA-carboline, showed similar uptake in the lungs of both fibrotic and control mice. Conclusion: We demonstrated that a small molecule PET probe can be applied for the molecular imaging of active Fibrogenesis. Research Support: This project is supported by the National Institutes of Health (EB009062, HL131907, RR029495). JW is supported by the German Research Foundation (DFG). References: 1. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med.2013, 5:167sr161. 2. Chen HH, Waghorn PA, Wei L, Tapias LF, Schu Hle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic Fibrogenesis JCI Insight.2017, 2. 3. Waghorn PA, Jones CM, Rotile NJ, Koerner SK, Ferreira DS, Chen HH, Probst CK, Tager AM, Caravan P. Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe Angew Chem Int Ed Engl.2017, 56:9825-9828.
Scott L. Friedman - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of hepatic Fibrogenesis
Best Practice & Research in Clinical Gastroenterology, 2011Co-Authors: Ursula E Lee, Scott L. FriedmanAbstract:Multiple etiologies of liver disease lead to liver fibrosis through integrated signaling networks that regulate the deposition of extracellular matrix. This cascade of responses drives the activation of hepatic stellate cells (HSCs) into a myofibroblast-like phenotype that is contractile, proliferative and fibrogenic. Collagen and other extracellular matrix (ECM) components are deposited as the liver generates a wound-healing response to encapsulate injury. Sustained Fibrogenesis leads to cirrhosis, characterized by a distortion of the liver parenchyma and vascular architecture. Uncovering the intricate mechanisms that underlie liver Fibrogenesis forms the basis for efforts to develop targeted therapies to reverse the fibrotic response and improve the outcomes of patients with chronic liver disease.
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reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver Fibrogenesis in vivo
Gastroenterology, 2010Co-Authors: Joy X Jiang, Senthil K Venugopal, Nobuko Serizawa, Xiangling Chen, Fiona Scott, R H Adamson, Sridevi Devaraj, Vijay Shah, Eric M Gershwin, Scott L. FriedmanAbstract:Background & Aims Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in Fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to Fibrogenesis, our aim was to study the phagocytic NADPH oxidase NOX2. Methods An in vivo phagocytosis model was developed by injecting wild type (wt) or NOX2 −/− mice with lentiviral-green fluorescence protein (GFP) containing a hepatocyte-specific promoter, and adeno-tumor necrosis factor-related apoptosis-inducing ligand (ad-TRAIL). Fibrosis was evaluated in bile duct ligated (BDL) wt and NOX2 −/− mice with or without gadolinium treatment. NOX2 expression was studied in human liver samples and in HSC isolated from fibrotic livers. The fibrogenic activity of NOX2 was assessed by collagen reporter assays. Results In the phagocytosis model, engulfment of GFP-labeled apoptotic bodies was seen, and the expression of α-smooth muscle actin (α-SMA) and collagen I increased significantly in the wt but not in the NOX2 −/− mice. Inhibiting apoptosis decreased the profibrogenic response. NOX2 −/− animals exhibited significantly less fibrosis following BDL. Inactivating macrophages in wt BDL mice did not lower collagen production to the level observed in NOX2 −/− mice, suggesting that NOX2-expressing HSC are important in Fibrogenesis. NOX2 was up-regulated in HSC from fibrotic livers, and phagocytosis-induced NOX2 expression and activity were demonstrated. Based on reporter assays, production of NOX2-mediated reactive oxygen species directly induced collagen promoter activity in HSC. Conclusions Apoptosis and phagocytosis of hepatocytes directly induce HSC activation and initiation of fibrosis. NOX2, the phagocytic NADPH oxidase, plays a key role in this process and in liver Fibrogenesis in vivo.
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mechanisms of hepatic Fibrogenesis
Gastroenterology, 2008Co-Authors: Scott L. FriedmanAbstract:Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5–10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow–derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of Fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.
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Cytokines and Fibrogenesis.
Seminars in Liver Disease, 2008Co-Authors: Scott L. FriedmanAbstract:: Cytokines play a major role in the development of hepatic fibrosis, the wound-healing response of the liver to chronic injury. Major concepts in defining the role of cytokines in Fibrogenesis include (1) Cytokines may be pro- or antifibrogenic; (2) autocrine, paracrine, and matrix-bound sources of cytokines are the most important; and (3) multiple mechanisms of cytokine regulation are essential to fine-tune their effects. The hepatic stellate cell is the key effector of the fibrotic response and both a principal source and target of cytokines. Activation of stellate cells connotes the conversion of a resting vitamin A-rich cell to one which is proliferative, contractile, fibrogenic, and devoid of vitamin A. The features of stellate cell activation provide a framework in which to understand how cytokines drive fibrosis. These features include (1) proliferation; (2) contractility; (3) Fibrogenesis; (4) extracellular matrix degradation; (5) chemotaxis; (6) cytokine release; and (7) retinoid loss. The insights gained from illuminating the role of stellate cells has engendered realistic hopes for treating hepatic fibrosis through modulation of cytokine actions.
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bmp 7 opposes tgf β1 mediated collagen induction in mouse pulmonary myofibroblasts through id2
American Journal of Physiology-lung Cellular and Molecular Physiology, 2006Co-Authors: Nobuhiro Izumi, Norifumi Kawada, Scott L. Friedman, Yuji Nakajima, Shinjiro Mizuguchi, Yutaka Inagaki, Shizuya Saika, Kiyotoshi Inoue, Shigefumi Suehiro, Kazuo IkedaAbstract:Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principal matrix-producing cells during pulmonary Fibrogenesis. Transforming growth factor (TGF)-β signaling plays an important ...