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      Assessing the Relationship between Lung Density and Function with Oxygen-Enhanced Magnetic Resonance Imaging in a Mouse Model of Emphysema

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          Abstract

          Purpose

          A magnetic resonance imaging method is presented that allows for the simultaneous assessment of oxygen delivery, oxygen uptake, and parenchymal density. The technique is applied to a mouse model of porcine pancreatic elastase (PPE) induced lung emphysema in order to investigate how structural changes affect lung function.

          Method

          Nine-week-old female C57BL6 mice were instilled with saline or PPE at days 0 and 7. At day 19, oxygen delivery, oxygen uptake, and lung density were quantified from T1 and proton-density measurements obtained via oxygen-enhanced magnetic resonance imaging (OE-MRI) using an ultrashort echo-time imaging sequence. Subsequently, the lungs were sectioned for histological observation. Blood-gas analyses and pulmonary functional tests via FlexiVent were performed in separate cohorts.

          Principal Findings

          PPE-challenged mice had reduced density when assessed via MRI, consistent with the parenchyma loss observed in the histology sections, and an increased lung compliance was detected via FlexiVent. The oxygenation levels, as assessed via the blood-gas analysis, showed no difference between PPE-challenged animals and control. This finding was mirrored in the global MRI assessments of oxygen delivery and uptake, where the changes in relaxation time indices were matched between the groups. The heterogeneity of the same parameters however, were increased in PPE-challenged animals. When the oxygenation status was investigated in regions of varying density, a reduced oxygen-uptake was found in low-density regions of PPE-challenged mice. In high-density regions the uptake was higher than that of regions of corresponding density in control animals. The oxygen delivery was proportional to the oxygen uptake in both groups.

          Conclusions

          The proposed method allowed for the regional assessment of the relationship between lung density and two aspects of lung function, the oxygen delivery and uptake. When compared to global indices of lung function, an increased sensitivity for detecting heterogeneous lung disorders was found. This indicated that the technique has potential for early detection of lung dysfunction–before global changes occur.

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          Most cited references33

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          CT-based Biomarker Provides Unique Signature for Diagnosis of COPD Phenotypes and Disease Progression

          Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers are urgently needed to enable individualized treatment thus improving patient outcome. We adapted the Parametric Response Map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole lung CT scans of 194 COPD individuals acquired at inspiration and expiration from the COPDGene Study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype, while providing detailed spatial information of disease distribution and location. PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients complementing standard clinical techniques.
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            Optimized 3D ultrashort echo time pulmonary MRI.

            To optimize 3D radial ultrashort echo time MRI for high resolution whole-lung imaging.
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              Noninvasive assessment of regional ventilation in the human lung using oxygen-enhanced magnetic resonance imaging.

              The imaging of regional ventilation in the lungs is essential for the evaluation of a variety of pathological conditions, such as emphysema, pneumonia and pulmonary embolism. We propose a novel approach for ventilation scanning, using magnetic resonance imaging (MRI) and inhaled molecular oxygen as a contrast agent, that directly depicts transfer of oxygen across the alveolus into the pulmonary vasculature. Molecular oxygen is only weakly paramagnetic but produces substantial signal changes in the lungs because of their large surface area. Ventilation defects were shown in a patient with bullous emphysema, and ventilation-perfusion mismatches were shown in two patients with pulmonary embolism.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 March 2016
                2016
                : 11
                : 3
                : e0151211
                Affiliations
                [1 ]Personalised Healthcare and Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden
                [2 ]Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden
                [3 ]Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden
                [4 ]Drug Safety and Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden
                [5 ]MedTech West, Chalmers University of Technology, Gothenburg, Sweden
                Research Center Borstel, GERMANY
                Author notes

                Competing Interests: The funder, AstraZeneca R&D, provided support in the form of salaries for authors [MZ, LS, EJ, GM, PH, SJ, HZ, MO], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: MZ LS GM PDH. Performed the experiments: MZ LS SJ. Analyzed the data: MZ SJ HZ. Contributed reagents/materials/analysis tools: MZ EJ MO SJ. Wrote the paper: MZ MO EJ.

                Article
                PONE-D-15-43162
                10.1371/journal.pone.0151211
                4792441
                26977928
                8a7e3a23-d358-4ec3-a61b-37e6d42c20c0
                © 2016 Zurek et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 October 2015
                : 23 February 2016
                Page count
                Figures: 5, Tables: 3, Pages: 14
                Funding
                This work was supported by ITN Marie Curie, FP7-ITN PINET; Grant number: PITN-GA-2010-264864. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Elements
                Oxygen
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Pulmonary Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Pulmonary Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Pulmonary Imaging
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Emphysema
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Hematology
                Blood
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Respiration
                Breathing
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Respiration
                Breathing
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                All relevant data are within the paper.

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