Diseases of the Chest, Breast, Heart and Vessels 2019-2022

This open access book focuses on diagnostic and interventional imaging of the chest, breast, heart, and vessels. It consists of a remarkable collection of contributions authored by internationally respected experts, featuring the most recent diagnostic developments and technological advances with a highly didactical approach. The chapters are disease-oriented and cover all the relevant imaging modalities, including standard radiography, CT, nuclear medicine with PET, ultrasound and magnetic resonance imaging, as well as imaging-guided interventions. As such, it presents a comprehensive review of current knowledge on imaging of the heart and chest, as well as thoracic interventions and a selection of "hot topics". The book is intended for radiologists, however, it is also of interest to clinicians in oncology, cardiology, and pulmonology

Diseases of the Chest, Breast, Heart and Vessels 2019-2022

This open access book focuses on diagnostic and interventional imaging of the chest, breast, heart, and vessels. It consists of a remarkable collection of contributions authored by internationally respected experts, featuring the most recent diagnostic developments and technological advances with a highly didactical approach. The chapters are disease-oriented and cover all the relevant imaging modalities, including standard radiography, CT, nuclear medicine with PET, ultrasound and magnetic resonance imaging, as well as imaging-guided interventions. As such, it presents a comprehensive review of current knowledge on imaging of the heart and chest, as well as thoracic interventions and a selection of "hot topics". The book is intended for radiologists, however, it is also of interest to clinicians in oncology, cardiology, and pulmonology

Pulmonary fibrosis: one manifestation, various diseases

This research topic collection entitled “Pulmonary Fibrosis: one manifestation, various diseases”, involving authors from different countries, confirms that this disease is a hot topic (Confalonieri P et al.,2022, Orlandi M et al., 2022). There are over 200 different types of pulmonary fibrosis (PF), the most common is the idiopathic pulmonary fbrosis (IPF), called idiopathic because it has no known cause. Another rare form is familial PF, for which several studies reported correlation with few genes. An important group of PF are due to other diseases, for example, autoimmune diseases such as rheumatoid arthritis, systemic sclerosis or Sjogren’s syndrome (Ruaro et al., 2022, Trombetta AC et al., 2017, Bernero Eet al., 2013). PF could correlate to viral infections (e.g. COVID-19), gastroesophageal reflux disease (GERD) (Baratella E et al, 2021, Ruaro et al., 2018), and the exposure to various materials (including naturally occurring such as bird or animal droppings, and occupational such as asbestos or silica). Furthermore, smoking, radiation treatments, and certain drugs can increase risk of developing PF. In the first article (Saketkoo et al.) of the collection, the authors evaluate the use of International Classification of Functioning, Disability, and Health (ICF) approved by World Health Organization (WHO) in patients affected by interstitial lung diseases (ILD)

Quantification of chronic fibrosing interstitial pneumonia on computed tomography

The chronic fibrosing interstitial pneumonias (CFIPs) are diseases which cause progressive and often fatal progressive scarring of the lungs. The recent discovery of the first effective pharmacological therapies for this condition have increased interest in the monitoring of this disease. Due to the complex appearance of the CFIPs on computed tomography, visual quantification of disease severity and extent is limited. The purpose of this thesis was to develop and test a computer algorithm for the automated quantification of pulmonary fibrosis on CT using textural measures known as Minkowski functionals. A computer algorithm was successfully developed and this thesis presents initial results of testing the algorithm on a series of normal scans and on 24 prospectively recruited patients who also underwent a series of other tests including pulmonary function tests and a patient reported symptom questionnaire. The computer output was also compared with the visual assessment of two radiologists. Significant correlations were found between computer calculated lung volume and total lung capacity as measured on pulmonary function tests. We also found a significant correlation between computer calculated fibrosis volume and both gas transfer and forced vital capacity. The radiologists’ visual assessment of fibrosis and the computer estimated fibrosis volume were highly correlated. The novel computer algorithm represents a promising method for quantifying pulmonary fibrosis on CT with potential roles in monitoring disease progression and effects of therapeutic interventions

Three-Dimensional Fractal Analysis of Idiopathic Pulmonary Fibrosis

The characterization of lung tissue architecture in Idiopathic Pulmonary Fibrosis (IPF) can provide useful insights into disease presentation and progression. In this study, we propose a novel three-dimensional (3D) fractal analysis to quantify the behavior of lung tissue in both healthy and bleomycin (BLM)-induced fibrotic mouse models. The fractal dimension (FD), which is a statistical index of complexity, was calculated for each voxel in reconstructed micro-CT images of the lung samples. These values were plotted on a kernel density estimation (KDE) plot, generating a distribution of FDs for each sample. Results indicate a slight but not statistically significant difference in average FD between the control and BLM samples. Tissue densities between the two groups were also compared in Hounsfield units (HU), a radiodensity scale, revealing elevated collagen concentrations and peripheral fibrosis in the BLM groups, consistent with IPF. Due to our small sample size of only 9 mouse lungs, further conclusions about the structural differences between healthy and fibrotic lungs are impaired. However, the results suggest disparities in the organization and/or collagen density between groups. Therefore, further assessments encompassing density features into the FD may prove to be an effective mode for differentiating and/or describing healthy and IPF lungs

The extracellular matrix protein fibulin-1 in idiopathic pulmonary fibrosis

One of the most pressing issues in the clinical management of patients with idiopathic pulmonary fibrosis (IPF) is how a clinician can respond when asked “how long do I have?” IPF has a varied clinical course and the only available treatments, aside from lung transplantation, are corticosteroids and immunosuppressants. The side effects of both corticosteroids and immunosuppressants may actually outweigh the benefits for use in IPF. Biomarkers of disease progression are often unable to predict acute lung function decline. This is possibly because the underlying mechanisms driving the disease are poorly understood and little attention has been paid to how intrinsic differences in resident lung fibroblasts may be contributing to this disease. In this thesis, extracellular matrix (ECM) molecules that are both found in the blood and released by resident lung fibroblasts were investigated for their utility as biomarkers of disease progression in IPF. The primary focus was on the ECM protein fibulin-1, an essential constituent of elastic fibres, which has not previously been studied in the context of interstitial lung disease. This thesis investigated the relationship between fibulin-1, and disease severity in patients with and without pulmonary fibrosis. In addition, the utility of fibulin-1 as a biomarker of disease progression was compared against other previously described components of the ECM, namely periostin, tenascin-C and fibronectin, in the same patients. Lastly, the effect of the profibrotic cytokine transforming growth factor-beta-1 (TGFβ1) on fibulin-1 levels in resident lung fibroblasts from patients with and without IPF was interrogated

Biomarker discovery and drug testing in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating and lethal disease, with a median survival of 2-3 years after diagnosis. It is chronic, progressive and occurs predominantly in middle-age and older adults. Multiple working hypotheses speak of possible triggers of IPF development, e.g. multiple microinjuries of the alveolar epithelium, aberrant fibroblast activation, and immune deregulation. Currently, there are two drugs approved for the treatment of mild-to-moderate IPF worldwide, neither Pirfenidone or Nintedanib provide a definitive cure for disease, but slow in disease progression. Thus, animal models of pulmonary fibrosis are a critical tool for disease understanding, drug development and pre-clinical intervention. In chapter 2.1, the first study included in this thesis (Fernandez et al., 2016a), we comprehensively analyzed IPF-relevant peripheral biomarkers, histological compromise along with physiological parameters, to determine disease onset, progression and resolution in preclinical models of fibrosis. We observed and validated that the bleomycin-induced pulmonary fibrosis model reached its peak of fibrosis 14 days after treatment and from there on, resolution started. Furthermore, we created a semi-automatized histologic scoring system to quantify the degree of fibrosis, and correlated histology score with lung function decline during the initiation, peak and resolution phase of the model. Interestingly, we observed that at day 28 and 56 although histological compromise was still present, lung function was close to normal. Furthermore, we determine that plasma levels of ICAM-1 strongly correlate with the extent of fibrosis. We complemented and extended our characterization of the model further. In a following study, we performed multi-compartmental deep proteomics in lung tissue and bronchoalveolar lavage (Schiller, Fernandez et al., 2015), with emphasis on characterizing the matrisome, from the initiation to the resolution of bleomycin-induced fibrosis, in where we could determine the initial signatures of injury, as well as the ones that drive lung repair. In chapter 2.2, we highlighted the second study of this thesis (Sun et al., 2015), that goes along with a complementary publication of our authorship. We use the ability of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to simultaneously record the distribution of hundreds of molecules, in a highly multiplexed and unbiased manner. After oral administration of pirfenidone, we could detect, visualize, and quantify the pharmacokinetics and in-situ distribution of pirfenidone in lung, liver and kidney from unchallenged mice. Furthermore, we performed analysis in fibrotic mice and IPF patients, untreated and under pirfenidone therapy (Sun*, Fernandez* et al. 2018). As expected, we detected mouse and human specific and shared responses; specific alterations of metabolite pathways in fibrosis, and most importantly, metabolic recalibration following pirfenidone treatment. Taking together, bleomycin-induced pulmonary fibrosis is an extremely valuable tool for preclinical drugs evaluation, as well as for target validation and modulation of Idiopathic Pulmonary Fibrosis.Die idiopathische pulmonale Fibrose ist eine schwerwiegende und tödlich verlaufende Erkrankung mit einer durchschnittlichen Lebenserwartung von zwei bis drei Jahren nach Diagnosestellung. Die chronisch progressive Erkrankung tritt vorwiegend im mittleren Lebensalter sowie bei älteren Erwachsenen auf. Zahlreiche Arbeitshypothesen zeigten mögliche Auslöser der IPF auf, wie beispielsweise Mikroverletzungen des Alveolarepithels, eine gestörte Fibroblastenaktivierung sowie eine Fehlregulation des Immunsystems. Derzeit sind weltweit zwei Medikamente zur Behandlung von leichter bis mittelschwerer IPF zugelassen, Pirfenidon und Nintedanib. Beide Medikamente verlangsamen den Verlauf der Erkrankung führen jedoch zu keiner Heilung. Somit sind Tiermodelle der Lungenfibrose ein wichtiges Werkzeug für das Verständnis von Krankheiten, die Arzneimittelentwicklung und präklinische Intervention. Kapitel 2.1 fasst die erste Publikation dieser Arbeit zusammen. In Fernandez et al. 2016 analysierten wir IPF-relevante periphere Biomarker und führten einen histologischen Vergleich mit physiologischen Parametern durch, um die Entstehung der Erkrankung, den Verlauf und die Resolution in präklinischen Modellen der Fibrose zu bestimmen. Unsere Ergebnisse zeigten, dass die Fibrose im bleomycininduzierten Modell der Fibrose ihren Höhepunkt an Tag 14 nach Belomycinbehandlung erreichte und danach die Phase der Resolution begann. Wir generierten ein semi-automatisiertes histologisches Bewertungssystem um den Grad der Fibrose zu quantifizieren und korrelierten diesen Wert mit der Abnahme der Lungenfunktion während der Initiierungsphase, der maximalen Fibrose und der Resolutionsphase des Models. Interessanterweise beobachteten wir an Tag 28 und 56 eine nahezu normale Lungenfunktion, obwohl histologische Auffälligkeiten noch immer vorhanden waren. Wir entdeckten, dass die Plasmaspiegel von ICAM-1 stark mit dem Fibrosegrad korrelierten. Wir erweiterten die Charakterisierung des Fibrosemodells und schlossen eine weitere Studie an, in der wir eine multi-kompartmentelle tiefgehende Proteomanalyse von Lungengewebe und bronchoalveolären Lavagen durchführten. Der Fokus lag dabei auf der Charakterisierung des Matrisoms von der Initiierungs- bis zur Resolutionsphase der bleomycininduzierten Fibrose. Wir konnten die anfänglichen Signaturen der Verletzung bestimmen, sowie diejenigen, die die Lungenreparatur antreiben Kapitel 2.2 hebt die zweite Publikation der vorliegenden Arbeit hervor, Sun et al., 2015, der eine Koautorenschaft zugrunde liegt. Hierbei nutzten wir die Methode der Matrix–Assistierten Laser–Desorptions/Ionisierungs Massenspektrometrie Bildgebung (Imaging) (MALDI-MSI), welche es ermöglicht in einem multiplexen und ungezielten Ansatz simultan die Verteilung hunderter Moleküle zu messen. Nach oraler Gabe von Pirfenidon, visualisierten und quantifizierten wir die gemessene Pharmakokinetik und in situ Verteilung von Pirfenidon in Lunge, Leber und Niere von gesunden Mäusen. Zusätzlich analysierten wir fibrotische Mäuse und IPF-Patienten, unbehandelt als auch unter Pirfenidontherapie (Sun*, Fernandez* et al. 2018). Wie erwartet entdeckten wir sowohl maus- und menschspezifische als auch gemeinsame Reaktionen, bezüglich spezifischer Änderungen metabolischer Prozesse in Fibrose und, von besonderer Bedeutung, der metabolischen Neukalibrierung nach Pirfenidonbehandlung. Zusammengefasst ist das Tiermodell der bleomycininduzierten pulmonalen Fibrose ein wichtiges Werkzeug für die präklinische Arzneimittelbewertung, sowie für die Validierung potentieller Zielmoleküle und einer Modulation der idiopathischen pulmonalen Fibrose

Review of hyperpolarized pulmonary functional 129Xe MR for long-COVID

The respiratory consequences of acute COVID-19 infection and related symptoms tend to resolve 4 weeks post-infection. However, for some patients, new, recurrent, or persisting symptoms remain beyond the acute phase and persist for months, post-infection. The symptoms that remain have been referred to as long-COVID. A number of research sites employed 129Xe magnetic resonance imaging (MRI) during the pandemic and evaluated patients post-infection, months after hospitalization or home-based care as a way to better understand the consequences of infection on 129Xe MR gas-exchange and ventilation imaging. A systematic review and comprehensive search were employed using MEDLINE via PubMed (April 2023) using the National Library of Medicine's Medical Subject Headings and key words: post-COVID-19, MRI, 129Xe, long-COVID, COVID pneumonia, and post-acute COVID-19 syndrome. Fifteen peer-reviewed manuscripts were identified including four editorials, a single letter to the editor, one review article, and nine original research manuscripts (2020–2023). MRI and MR spectroscopy results are summarized from these prospective, controlled studies, which involved small sample sizes ranging from 9 to 76 participants. Key findings included: 1) 129Xe MRI gas-exchange and ventilation abnormalities, 3 months post-COVID-19 infection, and 2) a combination of MRI gas-exchange and ventilation abnormalities alongside persistent symptoms in patients hospitalized and not hospitalized for COVID-19, 1-year post-infection. The persistence of respiratory symptoms and 129Xe MRI abnormalities in the context of normal or nearly normal pulmonary function test results and chest computed tomography (CT) was consistent. Longitudinal improvements were observed in long-term follow-up of long-COVID patients but mean 129Xe gas-exchange, ventilation heterogeneity values and symptoms remained abnormal, 1-year post-infection. Pulmonary functional MRI using inhaled hyperpolarized 129Xe gas has played a role in detecting gas-exchange and ventilation abnormalities providing complementary information that may help develop our understanding of the root causes of long-COVID

The role of nicotine, a7 nicotinic acetylcholine receptors and extracellular matrix remodeling in pulmonary fibrosis.

The median survival for idiopathic pulmonary fibrosis (IPF) patients from diagnosis is a dismal 3 years. This condition is characterized by pulmonary fibroproliferation and excess production and disordered deposition of extracellular matrix (ECM) proteins resulting in obliteration of the original tissue architecture, loss of lung function and eventual death due to respiratory failure. The main hindrance to the development of effective treatments against pulmonary fibrosis is the late detection of its progression and is often of unknown cause. Tobacco smoke represents the most important environmental factor linked to the development of pulmonary fibrosis, with over 60% of IPF patients current or ex-smokers, yet exactly how tobacco influences lung injury and repair is unknown. Research in this area has been hampered by the fact that tobacco is a very complex substance, containing thousands of chemicals. Due to this complexity, I have pursued a different approach and focused on factors, specifically nicotine, which might render the lung susceptible to fibrosis and contribute to the early pathophysiology of IPF. In this dissertation, I extend the work of Dr. Jesse Roman’s lab to investigate additional extracellular matrix modifications via nicotine exposure, including collagen type I. Investigating the cellular receptors and molecular mechanisms mediating the effects of nicotine on fibroblast collagen production/deposition and the potential role of nicotine-induced remodeling in rendering the host susceptible to pulmonary fibrosis are explored through 5 chapters: 1) The effects of nicotine on lung fibroblast proliferation and collagen expression/deposition in vitro and in vivo, and the cholinergic receptors responsible for these effects. 2) The effects of chronic nicotine exposure on injury-induced fibrosis. 3) The impact of chronic nicotine exposure on survival after bleomycin-lung injury. 4) A new diagnostic physiological formula for earlier detection of pulmonary fibrosis progression in IPF patients. 5) A clinical review on Hermansky-Pudlak syndrome, an orphan disease characterized by the natural formation of pulmonary fibrosis. This work provides a detailed understanding of the mechanisms by which tobacco promotes lung remodeling, leading to the development of better tools for diagnostic tracking, care and treatment of these patients

Novel 129Xe Magnetic Resonance Imaging and Spectroscopy Measurements of Pulmonary Gas-Exchange

Gas-exchange is the primary function of the lungs and involves removing carbon dioxide from the body and exchanging it within the alveoli for inhaled oxygen. Several different pulmonary, cardiac and cardiovascular abnormalities have negative effects on pulmonary gas-exchange. Unfortunately, clinical tests do not always pinpoint the problem; sensitive and specific measurements are needed to probe the individual components participating in gas-exchange for a better understanding of pathophysiology, disease progression and response to therapy. In vivo Xenon-129 gas-exchange magnetic resonance imaging (129Xe gas-exchange MRI) has the potential to overcome these challenges. When participants inhale hyperpolarized 129Xe gas, it has different MR spectral properties as a gas, as it diffuses through the alveolar membrane and as it binds to red-blood-cells. 129Xe MR spectroscopy and imaging provides a way to tease out the different anatomic components of gas-exchange simultaneously and provides spatial information about where abnormalities may occur. In this thesis, I developed and applied 129Xe MR spectroscopy and imaging to measure gas-exchange in the lungs alongside other clinical and imaging measurements. I measured 129Xe gas-exchange in asymptomatic congenital heart disease and in prospective, controlled studies of long-COVID. I also developed mathematical tools to model 129Xe MR signals during acquisition and reconstruction. The insights gained from my work underscore the potential for 129Xe gas-exchange MRI biomarkers towards a better understanding of cardiopulmonary disease. My work also provides a way to generate a deeper imaging and physiologic understanding of gas-exchange in vivo in healthy participants and patients with chronic lung and heart disease