Profiling of DIILD in a Bleomycin Rat Model

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Gene expression and cellular profiling in a rat bleomycin model of drug-induced interstitial lung disease (DIILD) (Conference Abstract)

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Profiling of DIILD in a Bleomycin Rat Model

Gene expression and cellular profiling in a rat bleomycin model of drug-induced interstitial lung disease (DIILD)

Irma Mahmutovic Persson, Nina Fransén Pettersson, Jian Liu, Hanna Falk-Håkansson, Lars E. Olsson and Karin von Wachenfeldt - on behalf of the TRISTAN Consortium


ESR Conference 2020

Abstract

A large number of frequently prescribed drugs have the potential to cause DIILD. We have characterized a rat model of bleomycin-triggered DIILD, by gene profiling combined with flow cytometric characterization of immune cell populations in lungs over 28 days.


Methods & Results: Sprague-Dawley rats received a single dose of intratracheal bleomycin. Longitudinal imaging was performed (MRI and 18F-FDG-PET/CT) and BAL fluid, blood, lungs and spleen collected. Lung homogenates were used for analysis of gene expression (RT-qPCR), assessment of hydroxyproline content and for flow cytometric analysis of immune cell populations in lung. Early time points were dominated by pro-inflammatory gene expression. Interestingly, fibrosis related genes, such as Gremlin1, CTGF and TGFβs, were also up-regulated (p<0.001) during the inflammatory phase (d3-7). In addition, at later time points during the fibrosis phase (d14-28) inflammatory related genes such as CCL3 (p<0.01) and TNFα stayed up-regulated. Some genes, such as IL-4 and IL-5, revealed dual peaks at d7 and at d28. Animals identified by MRI to have more severe disease demonstrated a different gene profile compared to those with less disease.  Analysis of immune cell populations during the different stages of the disease showed increased numbers of eosinophils, neutrophils and NK cells at the early stages. Neutrophils and macrophages also showed up in a second cell-peak at d28.


Conclusion: Linking the pathological changes observed by imaging to gene expression patterns and immune cell profiles in the lung, has provided an increasing understanding of how biomarkers can be implemented to develop improved DIILD- and lung injury models.

Profiling of DIILD in a Bleomycin Rat Model
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Repeatability and correlation of 129Xe- and OE-MRI

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Repeatability and correlation of hyperpolarized xenon-129 and oxygen enhanced MRI parameters in healthy volunteers (Conference Abstract)

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Repeatability and correlation of 129Xe- and OE-MRI

Repeatability and correlation of hyperpolarized xenon-129 and oxygen enhanced MRI parameters in healthy volunteers

Paul J.C. Hughes, Marta Tibiletti, Matthew J. Heaton, Ho-Fung Chan Guilhem J. Collier, Matthew Austin, Laurie J. Smith, Jim Lithgow, Jo Naish, Jim M. Wild, Geoff J.M. Parker


ISMRM Conference 2020

Abstract

Introduction: Hyperpolarized xenon-129 (129Xe) is able to assess both structure and function of the lungs. Oxygen enhanced MRI (OE-MRI) is a low-cost and easier to implement proton MRI acquisition method that may provide alternative functional metrics to 129Xe. We studied the repeatability of 129Xe and OE-MRI parameters in a population of adult healthy volunteers, and evaluated the degree of correlation between the resulting metrics.

Discussion: All 129Xe metrics had bias close to zero, as assessed by Bland-Altman analysis, with the sub-voxel measures of ADC, LmD and RBC:TP being the most repeatable. Furthermore, all 129Xe metrics had narrow limits of agreement suggesting these metrics to be suitable for longitudinal assessment of patients. OE-VVF was the most repeatable OE-MRI metric, with the remaining three having reasonable repeatability, strongly influenced by one subject (HV03) who showed large variability between visits. The existence of a correlation between ΔPO2 and 129Xe ventilation heterogeneity measures in healthy volunteers requires further investigation. 

Conclusions: 129Xe and OE MRI metrics are reproducible and it is feasible to acquire images using both methods in volunteers.
 

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Repeatability and correlation of 129Xe- and OE-MRI
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On gamma variate fitting

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On gamma variate fitting for perfusion quantification in the lung (Conference Abstract)

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Perfusion quantification in the lung

On gamma variate fitting for perfusion quantification in the lung.

Marta Tibiletti, Jo Naish, Matthew J. Heaton, Paul Hughes, Jim Wild, Geoff JM Parker

 

ISMRM Conference 2020

Abstract

Imaging of the first pass of a contrast agent bolus through a tissue allows the measurement of blood flow (BF), blood volume (BV) and mean transit time (MTT). Application of first pass imaging to the lung with MRI has significant advantages over perfusion quantification with SPECT or CT. The majority of works on this topic apply a Singular Value Decomposition (SVD4) with or without a prior fit to a gamma variate (GV) function to the concentration-time curve. In this study we compare lung perfusion quantification with and without GV fitting in a population of patients with interstitial lung disease (ILD). We also compare results from two GV formulations, as described by Madsen and by Li.

The presence and choice of gamma variate fitting has an influence on perfusion parameters, but this is generally very small, except for mean transit time. GV1 is to be preferred to GV2 given the the lower dispersal of results and only minimally higher fitting residuals. Also, the observed correlations between perfusion MR parameters and lung function tests are similar between fitting with GV1 and no fit, suggesting that these approaches are broadly equivalent in practice.
 

PERFUSION QUANTIFICATION IN THE LUNG
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IB in animal models for DIILD

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Imaging Biomarkers in Animal Models of Drug-Induced Lung Injury: A Systematic Review

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Imaging Biomarkers in DIILD Models

Imaging Biomarkers in Animal Models of Drug-Induced Lung Injury: A Systematic Review

Irma Mahmutovic Persson, Karin von Wachenfeldt, John C Waterton, Lars E Olsson, On Behalf Of The Tristan Consortium


J Clin Med., 30 Dec 2020;10(1):107; doi:10.3390/jcm10010107

 

Abstract

For drug-induced interstitial lung disease (DIILD) translational imaging biomarkers are needed to improve detection and management of lung injury and drug-toxicity. Literature was reviewed on animal models in which in vivo imaging was used to detect and assess lung lesions that resembled pathological changes found in DIILD, such as inflammation and fibrosis. A systematic search was carried out using three databases with key words "Animal models", "Imaging", "Lung disease", and "Drugs". A total of 5749 articles were found, and, based on inclusion criteria, 284 papers were selected for final data extraction, resulting in 182 out of the 284 papers, based on eligibility. Twelve different animal species occurred and nine various imaging modalities were used, with two-thirds of the studies being longitudinal. The inducing agents and exposure (dose and duration) differed from non-physiological to clinically relevant doses. The majority of studies reported other biomarkers and/or histological confirmation of the imaging results. Summary of radiotracers and examples of imaging biomarkers were summarized, and the types of animal models and the most used imaging modalities and applications are discussed in this review. Pathologies resembling DIILD, such as inflammation and fibrosis, were described in many papers, but only a few explicitly addressed drug-induced toxicity experiments.

IMAGING BIOMARKERS FOR DIILD MODELS
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In vivo models of Drug Induced ILD; tools to study

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In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

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Conference Abstract: DIILD in vivo models

In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

Irma Mahmutovic Persson, Hanna Falk Håkansson, Per-Ola Önnervik, Janne Persson, Karin von Wachenfeldt, Lars E. Olsson - on behalf of the TRISTAN Consortium


ERS Lung Science Conference (LSC), 8-11 March 2018, Estoril, Portugal

 

Background

Drug safety is extremely important, yet many drugs on the market have the possibility to induce interstitial lung injury, also known as drug induced interstitial lung disease (DIILD), although they are not administered locally into the lung. Once DIILD starts to develop, patients are normally taken off the drug, and in more severe cases treated with glucocorticoids. As a result, the induced lung injury resolve in many patients while others continue to develop progressive disease. In order to improve drug development in the future, and also to understand how to better treat patients with progressive DIILD, additional studies are required to investigate the underlying mechanisms of e.g. cell and matrix interactions. Well characterized models are needed for evaluation and development of biomarkers in order to better understand and accordingly prevent the progression of DIILD. The work presented here is part of a larger effort supported by IMI aiming at developing and validating pre-clinical imaging biomarkers for DIILD (TRISTAN). As a first step, a robust Bleomycin model is developed by testing various doses of Bleomycin from different manufacturers, along with imaging-monitoring of disease progression correlating this to cell- and histology analyses.

CONFERENCE ABSTRACT: DIILD IN VIVO MODELS
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Systematic review: In vivo imaging in animal models

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Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

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Conference Abstract: DIILD Animal Models

Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Karin von Wachenfeldt, Kashmira Pindoria, Michael Haase, Simon Campbell, Juan X. Delgado, Mark Wright, John C. Waterton and Lars E. Olsson - on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 September 2018, Paris, France

 

Abstract

Translational Imaging Biomarkers (IB) are needed to avoid or manage drug-toxicity, resulting in drug-induced interstitial lung disease (DIILD). We reviewed the literature on in vivo imaging to detect and assess lung lesions in animal models with relevance to DIILD and with pathological changes resembling clinical DIILD.

CONFERENCE ABSTRACT: DIILD ANIMAL MODELS
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Imaging biomarkers of oedema and fibrosis in a rat

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Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

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Conference Abstract: Imaging of DIILD in rats

Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Anders Örbom, Per-Ola Önnervik, Karin von Wachenfeldt and Lars E. Olsson- on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 Septembr 2018, Paris, France

 

Background

Drugs used to treat various diseases may induce lung injury known as drug induced interstitial lung disease (DIILD). Clinical and pre-clinical studies within the TRISTAN-consortium are aimed at finding translational Imaging Biomarkers (IB) that can indicate progression of DIILD at an early stage. In the present in vivo study, magnetic resonance imaging (MRI) was applied along with analyses of lavage and lung tissue.

CONFERENCE ABSTRACT: IMAGING OF DIILD IN RATS
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Drug-Induced Interstitial Lung Disease: A Systematic Review

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Drug-Induced Interstitial Lung Disease: A Systematic Review

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DIILD Review

Drug-Induced Interstitial Lung Disease: A Systematic Review

Sarah Skeoch, Nicholas Weatherley , Andrew J. Swift, Alexander Oldroyd, Christopher Johns, Conal Hayton, Alessandro Giollo, James M. Wild, John C. Waterton, Maya Buch, Kim Linton, Ian N. Bruce, Colm Leonard, Stephen Bianchi and Nazia Chaudhuri


J. Clin. Med. 2018, 7(10), 356 doi: 10.3390/jcm7100356.

 

Background

Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. Methods: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. Results: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3–5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. Conclusions: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.

DIILD REVIEW
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Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted

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Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted MRI at baseline in patients with interstitial lung disease (Conference Abstract)

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Conference Abstract: Hyperpolarised 129xenon MRS in ILD

Hyperpolarised 129xenon MR spectroscopy and diffusion-weighted MRI at baseline in patients with interstitial lung disease (Conference Abstract)

James Eaden, Paul Hughes, Ho-Fung Chan, Guilhem Collier, Oliver Rodgers, Graham Norquay, Matthew Austin, Laurie Smith, Steve Renshaw, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff Parker, Stephen Bianchi, and Jim Wild


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

CONFERENCE ABSTRACT: HYPERPOLARISED 129XENON MRS IN ILD
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Evaluation of automatic methods for arterial input function extraction

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Evaluation of automatic methods for arterial input function extraction for perfusion quantification in the lung (Conference Abstract)

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Conference Abstract: Automated AIF extraction

Evaluation of automatic methods for arterial input function extraction for perfusion quantification in the lung (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Paul J.C. Hughes, Helen Marshall, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Ian Bruce, James Eaden, Stephen Bianchi, Jim M Wild, Geoff JM Parker


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: AUTOMATED AIF EXTRACTION
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