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Chronic lung diseases: prospects for regeneration and repair

Peter J. Barnes, Gary P. Anderson, Malin Fagerås, Maria G. Belvisi
European Respiratory Review 2021 30: 200213; DOI: 10.1183/16000617.0213-2020
Peter J. Barnes
1National Heart & Lung Institute, Imperial College London, London, UK
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  • For correspondence: p.j.barnes@imperial.ac.uk
Gary P. Anderson
2Lung Health Research Centre, University of Melbourne, Melbourne, Australia
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Malin Fagerås
3AstraZeneca, Gothenburg, Sweden
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Maria G. Belvisi
1National Heart & Lung Institute, Imperial College London, London, UK
4Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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  • FIGURE 1
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    FIGURE 1

    Causes, pathogenesis and opportunities for therapeutic intervention in a) COPD and b) idiopathic pulmonary fibrosis (IPF). CRP: C-reactive protein; ECM: extracellular matrix; miRNA: microRNA; mTOR: mammalian target of rapamycin.

Tables

  • Figures
  • TABLE 1

    Examples of emerging techniques to deliver therapy in patients with COPD and idiopathic pulmonary fibrosis (IPF) and their limitations

    TechniqueDescriptionUses and advances made with the techniqueCurrent limitations
    PROTACProteolysis-targeting chimaera that uses the cell's ubiquitin–proteasome system to target-specific proteins for degradation
    • Could induce the degradation of proteins previously considered “undruggable” [50]

    • Highly selective for the target protein, with rapid, effective and prolonged degradation of the target [51]

    • Valuable for mechanisms requiring precise targeting for degradation

    • Can only target a protein for degradation, not for modification

    CRISPRCan manipulate gene function through gene deletion, correction or replacement; enhancement of gene expression; base editing
    • Huge potential for target-specific genetic medication for gene therapy in COPD and IPF to target dysregulated genes or pathways (e.g. epigenetic changes to genes implicated in mucus hypersecretion in COPD) [52]

    • Concerns exist around safety and off-target effects; these are under investigation [53]

    Inhaled antisense oligonucleotidesSingle-stranded DNA or RNA (20–21 base pairs) complementary to the target mRNA
    • Knocks down the expression of the target gene [54]

    • Can modulate molecules that cannot be targeted using antibodies [54]

    • Inhalation could minimise toxicities associated with systemic exposure of antisense oligonucleotides [54]

    • Currently in the investigational stage

    • Intracellular delivery to the site of action is a challenge [54]

    Exosomes as delivery systemsA potential delivery system for nucleic acid drugs
    • Potential use in delivering drugs such as antagomirs or miRNA molecules, thanks to their low antigenicity and toxicity [55]

    • Could target particular cell types

    • In vitro and in vivo studies have shown promise in successfully delivering molecules [56]

    • Currently in the investigational stage

    PROTAC: proteolysis-targeting chimaera; CRISPR: clustered regularly interspaced short palindromic repeats.

    • TABLE 2

      Examples of new or emerging techniques for studying COPD and idiopathic pulmonary fibrosis (IPF)

      TechniqueDescriptionUses and advances made with the techniqueCurrent limitations
      Micro-CT imagingHigh-resolution CT imaging
      • Higher-resolution versus standard CT imaging [61]

      • Can reveal structural changes associated with small airway disease [61]

      • Reveals massive loss in number and area of terminal bronchioles in patients with centrilobular emphysematous COPD [6]

      • When partnered with parametric response mapping as an imaging biomarker, micro-CT could identify terminal bronchiole pathology in COPD [62]

      Performed on ex vivo samples, or explants, rather than on the patient [6, 61, 62]
      PETMolecular imaging; most commonly measuring 18F-FDG uptake
      • Has been explored as a noninvasive biomarker for pulmonary inflammation [63]

      • Ability to quantify inflammation is under investigation [63]

      Validation of imaging approaches required; changes in lung air, blood and water volumes depending on disease severity can cause variations in signals [63]
      Gas diffusion MRINoble gases such as 3He and 129Xe used to visualise lung structure
      • Could be used to monitor disease progression and response to therapy [59]

      • Can detect microstructural changes in the lung, even in asymptomatic smokers [59]

      • Quantitative microstructure data obtainable by measuring gas diffusion in alveoli; the technique can differentiate between patients with COPD and healthy individuals [64]

      • Alveolar sizes can be visualised to form a picture of alveolar loss in COPD [64]

      • Provides sensitive and reproducible data on gas exchange impairment in IPF, correlating with spirometry data [65]

      Adaption of existing scanners is required [66]
      SPECTRadiotracers used to image the lung, where both airways and blood flow can be imaged
      • Both the airways and blood flow can be imaged, allowing the detection of comorbidities such as pulmonary embolism [67, 68]

      • Can detect abnormalities in apparently healthy smokers [69]

      • Only semi-quantitative [69]

      • Not as high resolution as other imaging methods [68]

      • Takes a long time to acquire an image (e.g. 45 min) [68]

      IOSNoninvasive measurement of respiratory mechanics in response to pressure oscillations
      • A reliable tool for investigating proximal and peripheral airways resistance in patients with COPD [70]

      • Peripheral airway resistance and compliance using IOS closely linked to COPD severity and exacerbations [58]

      • Could be used as a screening tool for early-stage COPD [58]

      • Useful for patients who cannot perform spirometry manoeuvres [71]

      • The minimal clinically important difference in IOS parameters needs to be established

      OCTA high-resolution optical imaging method
      • Resolution down to micrometre scale [72]

      • Can be used to accurately measure distal airways [73]

      • Could detect early changes to the distal airways and appears to be more sensitive than CT [72, 73]

      • Ultrafine bronchoscopy (with sedation) required to reach the distal airways [73]

      Multiple-breath nitrogen washoutNoninvasive measurement of residual nitrogen in the airways to detect any abnormalities in gas distribution in the lung
      • Does not require maximal effort and can be used in a paediatric setting [74]

      • Provides information on abnormalities in the small airways, including terminal bronchioles [75]

      • Can detect abnormalities in early disease [76]

      • Limited standardisation, which impacts the availability of widely applicable reference values [75]

      BreathomicsExhaled breath analysis to detect changes in volatile organic compounds
      • Could be used to diagnose COPD and differentiate COPD from asthma [77]

      • May be able to predict disease progression [77]

      • Could help distinguish COPD phenotypes [77]

      • Results can be confounded by parameters such as medication use, comorbidities, smoking and study site [77]

      CT: computed tomography; PET: positron emission tomography; 18F-FDG: 18F-2-fluoro-2-deoxy-d-glucose; MRI: magnetic resonance imaging; SPECT: single-photon emission computed tomography; IOS: impulse oscillometry; OCT: optical coherence tomography.

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      Chronic lung diseases: prospects for regeneration and repair
      Peter J. Barnes, Gary P. Anderson, Malin Fagerås, Maria G. Belvisi
      European Respiratory Review Mar 2021, 30 (159) 200213; DOI: 10.1183/16000617.0213-2020

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      Chronic lung diseases: prospects for regeneration and repair
      Peter J. Barnes, Gary P. Anderson, Malin Fagerås, Maria G. Belvisi
      European Respiratory Review Mar 2021, 30 (159) 200213; DOI: 10.1183/16000617.0213-2020
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      • Article
        • Abstract
        • Abstract
        • Introduction
        • Limitations of current treatment approaches
        • Future treatment strategies for COPD and IPF
        • Dysregulated processes presenting opportunities for regeneration and repair
        • Lessons for the future
        • Conclusion
        • Acknowledgements
        • Footnotes
        • References
      • Figures & Data
      • Info & Metrics
      • PDF

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      • Mechanisms of lung disease
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