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PET imaging approaches for inflammatory lung diseases: Current concepts and future directions
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PET imaging approaches for inflammatory lung diseases: Current concepts and future directions Delphine L. Chen a,∗ , Mark L. Schiebler b , Jin Mo Goo c , Edwin J.R. van Beek d a Divisions of Radiological Sciences and Nuclear Medicine, Mallinckrodt Institute of Radiology, Campus Box 8225, 510S, Kingshighway Blvd, St. Louis, MO, USA b Department of Radiology, UW-Madison School of Medicine and Public Heath, Madison, WI, USA c Department of Radiology, Seoul National University, Seoul, Korea d Clinical Research Imaging Centre, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Article history: Received 6 September 2016 Accepted 15 September 2016 Keywords: Positron emission tomography COPD Pulmonary fibrosis Asthma 18 Fluorodeoxyglucose 18 Fluoro-fluciclatide 18 F-NOS
a b s t r a c t Inflammatory lung disease is one of the most common clinical scenarios, and yet, it is often poorly understood. Inflammatory lung disorders, such as chronic obstructive pulmonary diseases, which are causing significant mortality and morbidity, have limited therapeutic options. Recently, new treatments have become available for pulmonary fibrosis. This review article will describe the new insights that are starting to be gained from positron emission tomography (PET) methods, by targeting molecular processes using dedicated radiotracers. Ultimately, this should aid in deriving better pathophysiological classification of these disorders, which will ultimately result in better evaluation of novel therapies. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Many acute and chronic lung diseases are characterized by persistent lung inflammation. Lung parenchymal inflammation is caused by the complex response to various insults by the immune and vascular systems. The morphologic and functional changes in the lung parenchyma differ according to the stage of inflammation. While computed tomography (CT) clearly delineates the morphology of the normal and abnormal secondary lobule within the lung, it does not reflect the ongoing cellular activity or turnover that occurs during infection, malignancy, fibrosis or scarring. Magnetic resonance imaging (MRI) can similarly depict morphologic changes from lung parenchymal inflammation and provide additional information that may be able to discriminate inflammation from other processes without radiation exposure [1]. The promise of molecular imaging is several-fold: 1) To act as an early proxy for determining the presence of the beginning stages of inflammation that are not easily detected by CT morphologic or density changes, 2) To show whether or not medical therapy (or other intervention) has affected the progression of lung damage prior to irreversible pulmonary fibrosis with honey-combing, and 3) To enable mechanistic stud-
∗ Corresponding author. E-mail address: [email protected] (D.L. Chen).
ies of disease pathophysiology in humans, thus creating stronger links between the animal models used to study lung disease mechanisms and the activity of these molecular mechanisms in patients with lung disease. Positron emission tomography (PET) is thus wellsuited as molecularly targeted radiopharmaceuticals can be used to interrogate specific causes of inflammation in the lung and quantifying the relative activity of these inflammatory pathways (Fig. 1). Such radiopharmaceuticals can also be used to assess the treatment responses of targeted anti-inflammatory therapies. The pathophysiology of lung inflammation can be divided into two major groups: focal and diffuse. Within these broad categories are those that are restricted to the airways (tracheal bronchial tree and respiratory epithelium) and those that are located within the lung parenchyma, typically centered within the secondary lobule [2]. The disorders that cause focal intra-parenchymal inflammation are typically infectious. Focal inflammation of the airways is also frequently observed in acute and chronic inflammatory lung disease. Causes of airway inflammation include: air pollution, smoke, tobacco smoking, COPD and COPD exacerbation, viral inflammation, asthma, cystic fibrosis, immotile cilia syndrome, and chronic aspiration, mycobacterial tuberculosis and non-mycobacterial tuberculous infection. On the other hand, the causes of diffuse inflammation are rather protean. The most common causes of diffuse inflammation are related to the large number of entities that result in organizing pneumonia. Disorders that
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Fig. 1. 18 F FDG PET/CT lung images in a 62 year old man treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for Hodgkin lymphoma. The treatment monitoring scan obtained after two cycles of ABVD (top row) shows infiltrates with minimally increased 18 F FDG uptake in a few infiltrates in the right upper lobe. The post-treatment scan (bottom row) demonstrates not only a few additional infiltrates but also increased uptake within previously seen infiltrate. Additionally, there is diffusely increased uptake in the normal lung parenchyma on the post-treatment scan that was not present on the treatment monitoring scan. The etiology of this is unclear but could be related to a low-grade inflammatory response to bleomycin that did not lead to visible anatomic changes on the CT images. This example demonstrates how 18 F FDG uptake vary in the lungs in the absence of anatomic changes in the lungs. The presence of increased inflammation in the lungs post-treatment was further supported by the increased number of areas with infiltrate and associated increased 18 F FDG uptake. Each PET image is scaled to make the blood pool activity equal between the images (scaled to maximum standard uptake value (SUV) 1.8 for treatment monitoring scan, 2.0 for the post-treatment scan). Images were obtained at the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO.
cause idiopathic pulmonary fibrosis (IPF), interstitial pneumonias of non-specific interstitial pneumonia, acute interstitial pneumonia, usual interstitial pneumonia, respiratory bronchiolitis related lung disease, hypersensitivity pneumonia and organizing pneumonia are all part of this group. However, the mechanisms by which inflammation in these diseases causes lung dysfunction remains unknown. Therefore, assessing molecular functional information and anatomic information with PET and CT or MRI could yield important insights in demonstrating the structural and functional consequences of the underlying molecular activity that causes these changes. Although the inflammatory response itself is thought to cause or contribute to the progression of many chronic lung diseases, inflammation may also lead to other consequences or may be a bystander effect of other processes. For example, inflammation is associated with malignancy, particularly in idiopathic pulmonary fibrosis (IPF) [3]. The incidence of lung cancer in the setting of IPF is five times higher than the normal population and can be very difficult to diagnose by CT [3]. The combination of PET and CT in these cases is critical prior to sending the patient to biopsy as the biopsy itself can be associated with the initiation of an acute inflammatory response that leads to acute fibrinous organizing pneumonia and death. Furthermore, the fibrotic diseases themselves, such as IPF, were once thought to be driven by lung inflammation. However, the failure of steroids to alter the disease course demonstrate that inflammation may not be the central pathogenic process for IPF [4]. A growing body of data now support the hypothesis that fibrosis is caused by abnormal wound healing and repair responses to an initial epithelial insult [5]. Therefore, approaches that can interro-
gate inflammation and wound healing and repair responses could be useful in studying the relationship of these mechanisms in lung disease. This review will provide a brief summary of some of the PET imaging approaches being investigated to image molecular processes that are relevant to inflammatory lung diseases. The challenges for using these as molecular biomarkers for understanding disease mechanisms and for assessing treatment responses to targeted interventions will also be discussed. 2. 18 F-Fluorodeoxyglucose imaging with PET/CT for detecting and quantifying lung inflammation 18 F-Fluorodeoxyglucose
(18 F-FDG) is widely used for clinical oncologic imaging. FDG is a glucose analog that is trapped in cells following its first enzymatic step in the Krebs cycle, leading to 18 F FDGphosphate. Inflammatory lesions are the most frequent cause of false-positive lesions in these cancer diagnostic studies. Therefore, a number of studies have investigated its ability to quantify lung inflammation for the purpose of serving as a more sensitive treatment response marker to anti-inflammatory treatments. These include human studies investigating pneumonia, COPD, acute respiratory distress syndrome, and asthma. Understanding the mechanisms that lead to increased 18 F FDG uptake in inflammatory lesions is helpful in interpreting what its uptake means in the context of lung inflammation and targeted anti-inflammatory treatment. Increased glycolysis occurs in nearly all activated immune cell types. Neutrophils increase glucose uptake with priming and translocate the glucose transporter 18 F
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GLUT1 to the membrane upon activation with endotoxin [6,7]. As a result, increased 18 F FDG uptake in the lungs can be seen when neutrophils are primed, leading to margination in the pulmonary vasculature prior to neutrophil transendothelial migration into the airways [8,9]. Lymphocytes upregulate both oxidative phosphorylation and glycolysis upon antigen receptor-mediated activation, leading to increased 18 F FDG uptake during acute rejection of transplanted lungs [10,11]. Glycolytic activity in macrophages varies depending on the function of the macrophage as well as its local environment [12], with increased 18 F FDG uptake observed in macrophages recruited during sterile abscess formation and during endotoxin-mediated lung inflammation [13,14]. Eosinophils, like neutrophils, also increase glucose utilization in response to cytokine stimulation by increased translocation of several GLUT transporters [15]. Finally, other structural cell types within the lungs also increase glucose utilization during inflammation [14,16]. Therefore, 18 F FDG uptake likely serves as a marker of the global inflammatory response in the lungs.
3. New PET tracers for imaging lung inflammation 3.1. 18 F(+/−) NOS for imaging inducible nitric oxide synthase (iNOS) A new radiotracer for inducible nitric oxide synthase (iNOS), NOS, could be useful for imaging inflammation. Inducible nitric oxide synthase (iNOS) is one of three nitric oxide synthase isoforms that is constitutively expressed in lung epithelium [17] and which is also specifically induced by inflammation [18]. Inducible NOS is upregulated in response to endotoxin, tumor necrosis factor (TNF-␣), and other cytokines of the inflammatory pathway [19] and can contribute to oxidative stress as a result of excess production of nitric oxide, which can react rapidly with superoxide? dismutase (the production of which is also increased in response to inflammation) to form peroxynitrite, a powerful oxidant that leads to DNA damage and tissue injury [19]. Oxidative stress is increasingly being recognized as a potentially significant contributor to the development of acute respiratory distress syndrome (ARDS) and or acute lung injury (ALI) [20] and post-lung transplant bronchiolitis obliterans[21] as well as playing a role in many chronic lung diseases (asthma and COPD) [22]. In addition, iNOS is specifically induced by inflammation. Its expression is increased in a number of chronic lower respiratory diseases that are characterized by inflammation, correlating with the severity and progression of asthma [23,24], COPD [25–27], and ARDS [28,29]. Preclinical studies further suggest that iNOS may cause lung tissue destruction and remodeling that leads to fibrosis [30]. (Ref Harrari) Therefore, an imaging approach that can quantify iNOS levels could be highly useful for investigating the contribution of iNOS to the development of human lung diseases. 18 F(+/−)NOS is an iNOS-targeted PET tracer that was evaluated preclinically in an animal model of endotoxin-induced lung inflammation [31]. To demonstrate that this tracer could perform similarly in humans, Chen et al. assessed its ability to image endotoxin-induced lung inflammation in healthy volunteers [32]. One-hour dynamic 18 F(+/−)NOS PET images were obtained in healthy volunteers before and 16 h after the instillation of endotoxin in a single segment of the right lung (usually the lateral segment of the right middle lobe). Airway cells from the endotoxinchallenged segment were obtained by bronchoalveolar lavage and processed using enzyme linked immunohistochemical staining for iNOS. 18 F(+/−)NOS was quantified as the distribution volume ratio (DVR) using Logan plot analysis with a region placed over the pulmonary artery as the reference region and lung regions of interest placed using the airspaces disease found on the CT images as a 18 F(+/−)
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guide. The DVR increased in all volunteers except for one in whom iNOS was not detectable (Fig. 2). These pilot data support the specificity of 18 F(+/−)NOS uptake for imaging iNOS as the change in 18 F(+/−)NOS DVR appeared to depend on the presence iNOS. These data were particularly encouraging because the edema that occurs with inflammation can cause nonspecific retention of radiopharmaceuticals. In this case, 18 F(+/−)NOS was not retained despite the presence of edema, further supporting the potential utility of this tracer for imaging iNOS protein expression in the lungs and thus its contribution to the development of lung fibrosis. 3.2.
18 F-Fluciclatide
for imaging pulmonary fibrosis
Integrins are a group of molecules responsible for intercellular adhesion and signaling with a wide range of physiological and pathophysiological functions [33]. The integrin ␣v 3 is found at low levels on mature endothelial cells and is required for maintaining vascular permeability during acute lung inflammation [34]. However, this integrin is also markedly upregulated on activated fibroblasts, tumor cells and associated vasculature [35]. Indeed this receptor is believed to help drive the differentiation of fibroblasts into endothelial cells and myofibroblasts, with increased expression described in a number of pathological conditions associated with accelerated neovascularity, such as seen in cancer, and fibrosis including different forms of organ fibrosis and cardiovascular disease. Therefore, the imaging of this receptor could be a useful biomarker for quantifying (myo)fibroblast differentiation in IPF. Fluciclatide is an arginine-glycine-aspartic acid peptide with high affinity for ␣v 3 /␣v 5 integrin (with affinities (EC50) of 11.1 and 0.1 nM respectively), which has been radiolabeled with F-18 for PET imaging of angiogenesis and active fibrosis and evaluated in a Phase 1 trial [36]. More recently published in abstract form, 18 F-fluciclatide was evaluated in a study of 5 healthy volunteers, 14 patients with systemic sclerosis related interstitial pulmonary fibrosis and 9 patients with idiopathic pulmonary fibrosis to determine its effectiveness in demonstrating areas of presumed myofibroblast differentiation [37]. 18 F-fluciclatide PET imaging was correlated with CT chest findings. The whole lungs showed nearly twice the level of 18 F-fluciclatide uptake, as quantified using the maximum standard uptake value (SUV), in the participants with lung fibrosis compared to healthy volunteers, particularly in lung areas which demonstrated higher extent of fibrosis (Fig. 3). This initial study shows the potential for this PET agent used as an imaging biomarker to identify the beginning of myofibroblast differentiation and the ultimate development of pulmonary fibrosis. 3.3. Potential for PET tracers to serve as biomarkers for treatment response PET imaging tracers can be used not only to study the relationship of specific molecular pathways to lung disease, but also to assess treatment responses after the administration of molecularly targeted therapies. As such, determining the optimal method for determining PET tracer uptake that most accurately reflects the underlying biology is necessary to move these agents forward. However, this can be challenging as obtaining direct validation of the imaging target expression in the lungs is not always possible. Many patients cannot undergo lung biopsies or bronchoalveolar lavage without significant risks to their health. Furthermore, the lungs vary in density, which alone can change the intensity of the signal in the lungs. There have been several methods proposed to account for lung density changes [38,39]; however, the most appropriate method remains to be determined. To advance the development of new PET radiopharmaceuticals, early phase studies will likely need to focus either on studying subjects who have
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Fig. 2. PET/CT images demonstrating endotoxin-induced inducible nitric oxide (iNOS) expression with 18 F(+/−)NOS. Healthy volunteers imaged before and 16 h after instillation of endotoxin in the lateral segment of the right middle lobe demonstrate increased 18 F(+/−)NOS uptake, displayed as a parametric image of the distribution volume ratio (DVR) calculated by Logan plot analysis using the pulmonary artery as the reference region. The 18 F(+/−)NOS DVR increased in all volunteers with positive iNOS immunostaining on cells obtained by bronchoalveolar lavage (BAL); however, in one volunteer in which no iNOS could be detected by immunostaining, no change in 18 F(+/−)NOS uptake was noted after endotoxin (This research was originally published in JNM, reference [32], with figure modified with permission.).
Fig. 3. 18 F-Fluciclatide PET/CT imaging of a patient with aortic stenosis and incidental pulmonary fibrosis. 18 F-Fluciclatide PET CT was being performed to evaluate for endothelial change as a cause of aortic stenosis. A. The patient also had pulmonary fibrosis, evident on the CT images in the periphery of the lungs (arrows). B. 18 F-Fluciclatide uptake corresponds to fibrotic regions (arrows) with the scale in counts. This study was performed in the Clinical Research Imaging Centre (CRIC), University of Edinburgh (courtesy of Dr S. Mirsadraee).
mild disease and thus can tolerate the risks associated with obtaining tissue or use healthy volunteer models of lung disease in which correlating tissue specimens can be more easily obtained. However, tissue sampling has recognized limitations for serving as a gold standard. Another approach will be to compare different chemical entities that bind to the same biological target or are processed
in similar ways by the same enzyme. Obtaining correlative data from these different agents could then help cross-validate all of the different agents in the absence of a gold standard [40]. These approaches, together with obtaining intrasubject reproducibility data, will be needed to validate these agents as biomarkers for assessing treatment responses. Data from patients with and with-
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out treatment over time will be required to further validate the changes in uptake of these biomarkers, in correlation with structural and functional abnormality changes using CT and/or MRI and clinical symptoms and outcomes.
4. Conclusion We are now at the beginning of a new era of research using PET imaging to study the basic pathophysiology of lung inflammation. This modality has the potential to fill an unmet need for molecularly targeted biomarkers to assess the underlying lung disease mechanisms in patients. PET tracers can serve as noninvasive, quantitative, molecularly targeted biomarkers that can be used to serve as specific treatment response markers for targeted interventions. Combining the information from PET, CT, and MRI will provide investigators with novel tools to study the relationship between the activity of specific molecular pathways that result in alterations of lung structure and function.
Conflicts of interest None of the authors have any financial conflicts to disclose for this review article.
Acknowledgement DLC is funded by the National Institutes of Health (R01 HL121218, HL116389). Role of Funding Sponsor: DLC’s research efforts which contributed to this article.
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PET imaging approaches for inflammatory lung diseases: Current concepts and future directions Delphine L. Chen a,∗ , Mark L. Schiebler b , Jin Mo Goo c , Edwin J.R. van Beek d a Divisions of Radiological Sciences and Nuclear Medicine, Mallinckrodt Institute of Radiology, Campus Box 8225, 510S, Kingshighway Blvd, St. Louis, MO, USA b Department of Radiology, UW-Madison School of Medicine and Public Heath, Madison, WI, USA c Department of Radiology, Seoul National University, Seoul, Korea d Clinical Research Imaging Centre, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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Article history: Received 6 September 2016 Accepted 15 September 2016 Keywords: Positron emission tomography COPD Pulmonary fibrosis Asthma 18 Fluorodeoxyglucose 18 Fluoro-fluciclatide 18 F-NOS
a b s t r a c t Inflammatory lung disease is one of the most common clinical scenarios, and yet, it is often poorly understood. Inflammatory lung disorders, such as chronic obstructive pulmonary diseases, which are causing significant mortality and morbidity, have limited therapeutic options. Recently, new treatments have become available for pulmonary fibrosis. This review article will describe the new insights that are starting to be gained from positron emission tomography (PET) methods, by targeting molecular processes using dedicated radiotracers. Ultimately, this should aid in deriving better pathophysiological classification of these disorders, which will ultimately result in better evaluation of novel therapies. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Many acute and chronic lung diseases are characterized by persistent lung inflammation. Lung parenchymal inflammation is caused by the complex response to various insults by the immune and vascular systems. The morphologic and functional changes in the lung parenchyma differ according to the stage of inflammation. While computed tomography (CT) clearly delineates the morphology of the normal and abnormal secondary lobule within the lung, it does not reflect the ongoing cellular activity or turnover that occurs during infection, malignancy, fibrosis or scarring. Magnetic resonance imaging (MRI) can similarly depict morphologic changes from lung parenchymal inflammation and provide additional information that may be able to discriminate inflammation from other processes without radiation exposure [1]. The promise of molecular imaging is several-fold: 1) To act as an early proxy for determining the presence of the beginning stages of inflammation that are not easily detected by CT morphologic or density changes, 2) To show whether or not medical therapy (or other intervention) has affected the progression of lung damage prior to irreversible pulmonary fibrosis with honey-combing, and 3) To enable mechanistic stud-
∗ Corresponding author. E-mail address: [email protected] (D.L. Chen).
ies of disease pathophysiology in humans, thus creating stronger links between the animal models used to study lung disease mechanisms and the activity of these molecular mechanisms in patients with lung disease. Positron emission tomography (PET) is thus wellsuited as molecularly targeted radiopharmaceuticals can be used to interrogate specific causes of inflammation in the lung and quantifying the relative activity of these inflammatory pathways (Fig. 1). Such radiopharmaceuticals can also be used to assess the treatment responses of targeted anti-inflammatory therapies. The pathophysiology of lung inflammation can be divided into two major groups: focal and diffuse. Within these broad categories are those that are restricted to the airways (tracheal bronchial tree and respiratory epithelium) and those that are located within the lung parenchyma, typically centered within the secondary lobule [2]. The disorders that cause focal intra-parenchymal inflammation are typically infectious. Focal inflammation of the airways is also frequently observed in acute and chronic inflammatory lung disease. Causes of airway inflammation include: air pollution, smoke, tobacco smoking, COPD and COPD exacerbation, viral inflammation, asthma, cystic fibrosis, immotile cilia syndrome, and chronic aspiration, mycobacterial tuberculosis and non-mycobacterial tuberculous infection. On the other hand, the causes of diffuse inflammation are rather protean. The most common causes of diffuse inflammation are related to the large number of entities that result in organizing pneumonia. Disorders that
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Fig. 1. 18 F FDG PET/CT lung images in a 62 year old man treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for Hodgkin lymphoma. The treatment monitoring scan obtained after two cycles of ABVD (top row) shows infiltrates with minimally increased 18 F FDG uptake in a few infiltrates in the right upper lobe. The post-treatment scan (bottom row) demonstrates not only a few additional infiltrates but also increased uptake within previously seen infiltrate. Additionally, there is diffusely increased uptake in the normal lung parenchyma on the post-treatment scan that was not present on the treatment monitoring scan. The etiology of this is unclear but could be related to a low-grade inflammatory response to bleomycin that did not lead to visible anatomic changes on the CT images. This example demonstrates how 18 F FDG uptake vary in the lungs in the absence of anatomic changes in the lungs. The presence of increased inflammation in the lungs post-treatment was further supported by the increased number of areas with infiltrate and associated increased 18 F FDG uptake. Each PET image is scaled to make the blood pool activity equal between the images (scaled to maximum standard uptake value (SUV) 1.8 for treatment monitoring scan, 2.0 for the post-treatment scan). Images were obtained at the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO.
cause idiopathic pulmonary fibrosis (IPF), interstitial pneumonias of non-specific interstitial pneumonia, acute interstitial pneumonia, usual interstitial pneumonia, respiratory bronchiolitis related lung disease, hypersensitivity pneumonia and organizing pneumonia are all part of this group. However, the mechanisms by which inflammation in these diseases causes lung dysfunction remains unknown. Therefore, assessing molecular functional information and anatomic information with PET and CT or MRI could yield important insights in demonstrating the structural and functional consequences of the underlying molecular activity that causes these changes. Although the inflammatory response itself is thought to cause or contribute to the progression of many chronic lung diseases, inflammation may also lead to other consequences or may be a bystander effect of other processes. For example, inflammation is associated with malignancy, particularly in idiopathic pulmonary fibrosis (IPF) [3]. The incidence of lung cancer in the setting of IPF is five times higher than the normal population and can be very difficult to diagnose by CT [3]. The combination of PET and CT in these cases is critical prior to sending the patient to biopsy as the biopsy itself can be associated with the initiation of an acute inflammatory response that leads to acute fibrinous organizing pneumonia and death. Furthermore, the fibrotic diseases themselves, such as IPF, were once thought to be driven by lung inflammation. However, the failure of steroids to alter the disease course demonstrate that inflammation may not be the central pathogenic process for IPF [4]. A growing body of data now support the hypothesis that fibrosis is caused by abnormal wound healing and repair responses to an initial epithelial insult [5]. Therefore, approaches that can interro-
gate inflammation and wound healing and repair responses could be useful in studying the relationship of these mechanisms in lung disease. This review will provide a brief summary of some of the PET imaging approaches being investigated to image molecular processes that are relevant to inflammatory lung diseases. The challenges for using these as molecular biomarkers for understanding disease mechanisms and for assessing treatment responses to targeted interventions will also be discussed. 2. 18 F-Fluorodeoxyglucose imaging with PET/CT for detecting and quantifying lung inflammation 18 F-Fluorodeoxyglucose
(18 F-FDG) is widely used for clinical oncologic imaging. FDG is a glucose analog that is trapped in cells following its first enzymatic step in the Krebs cycle, leading to 18 F FDGphosphate. Inflammatory lesions are the most frequent cause of false-positive lesions in these cancer diagnostic studies. Therefore, a number of studies have investigated its ability to quantify lung inflammation for the purpose of serving as a more sensitive treatment response marker to anti-inflammatory treatments. These include human studies investigating pneumonia, COPD, acute respiratory distress syndrome, and asthma. Understanding the mechanisms that lead to increased 18 F FDG uptake in inflammatory lesions is helpful in interpreting what its uptake means in the context of lung inflammation and targeted anti-inflammatory treatment. Increased glycolysis occurs in nearly all activated immune cell types. Neutrophils increase glucose uptake with priming and translocate the glucose transporter 18 F
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GLUT1 to the membrane upon activation with endotoxin [6,7]. As a result, increased 18 F FDG uptake in the lungs can be seen when neutrophils are primed, leading to margination in the pulmonary vasculature prior to neutrophil transendothelial migration into the airways [8,9]. Lymphocytes upregulate both oxidative phosphorylation and glycolysis upon antigen receptor-mediated activation, leading to increased 18 F FDG uptake during acute rejection of transplanted lungs [10,11]. Glycolytic activity in macrophages varies depending on the function of the macrophage as well as its local environment [12], with increased 18 F FDG uptake observed in macrophages recruited during sterile abscess formation and during endotoxin-mediated lung inflammation [13,14]. Eosinophils, like neutrophils, also increase glucose utilization in response to cytokine stimulation by increased translocation of several GLUT transporters [15]. Finally, other structural cell types within the lungs also increase glucose utilization during inflammation [14,16]. Therefore, 18 F FDG uptake likely serves as a marker of the global inflammatory response in the lungs.
3. New PET tracers for imaging lung inflammation 3.1. 18 F(+/−) NOS for imaging inducible nitric oxide synthase (iNOS) A new radiotracer for inducible nitric oxide synthase (iNOS), NOS, could be useful for imaging inflammation. Inducible nitric oxide synthase (iNOS) is one of three nitric oxide synthase isoforms that is constitutively expressed in lung epithelium [17] and which is also specifically induced by inflammation [18]. Inducible NOS is upregulated in response to endotoxin, tumor necrosis factor (TNF-␣), and other cytokines of the inflammatory pathway [19] and can contribute to oxidative stress as a result of excess production of nitric oxide, which can react rapidly with superoxide? dismutase (the production of which is also increased in response to inflammation) to form peroxynitrite, a powerful oxidant that leads to DNA damage and tissue injury [19]. Oxidative stress is increasingly being recognized as a potentially significant contributor to the development of acute respiratory distress syndrome (ARDS) and or acute lung injury (ALI) [20] and post-lung transplant bronchiolitis obliterans[21] as well as playing a role in many chronic lung diseases (asthma and COPD) [22]. In addition, iNOS is specifically induced by inflammation. Its expression is increased in a number of chronic lower respiratory diseases that are characterized by inflammation, correlating with the severity and progression of asthma [23,24], COPD [25–27], and ARDS [28,29]. Preclinical studies further suggest that iNOS may cause lung tissue destruction and remodeling that leads to fibrosis [30]. (Ref Harrari) Therefore, an imaging approach that can quantify iNOS levels could be highly useful for investigating the contribution of iNOS to the development of human lung diseases. 18 F(+/−)NOS is an iNOS-targeted PET tracer that was evaluated preclinically in an animal model of endotoxin-induced lung inflammation [31]. To demonstrate that this tracer could perform similarly in humans, Chen et al. assessed its ability to image endotoxin-induced lung inflammation in healthy volunteers [32]. One-hour dynamic 18 F(+/−)NOS PET images were obtained in healthy volunteers before and 16 h after the instillation of endotoxin in a single segment of the right lung (usually the lateral segment of the right middle lobe). Airway cells from the endotoxinchallenged segment were obtained by bronchoalveolar lavage and processed using enzyme linked immunohistochemical staining for iNOS. 18 F(+/−)NOS was quantified as the distribution volume ratio (DVR) using Logan plot analysis with a region placed over the pulmonary artery as the reference region and lung regions of interest placed using the airspaces disease found on the CT images as a 18 F(+/−)
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guide. The DVR increased in all volunteers except for one in whom iNOS was not detectable (Fig. 2). These pilot data support the specificity of 18 F(+/−)NOS uptake for imaging iNOS as the change in 18 F(+/−)NOS DVR appeared to depend on the presence iNOS. These data were particularly encouraging because the edema that occurs with inflammation can cause nonspecific retention of radiopharmaceuticals. In this case, 18 F(+/−)NOS was not retained despite the presence of edema, further supporting the potential utility of this tracer for imaging iNOS protein expression in the lungs and thus its contribution to the development of lung fibrosis. 3.2.
18 F-Fluciclatide
for imaging pulmonary fibrosis
Integrins are a group of molecules responsible for intercellular adhesion and signaling with a wide range of physiological and pathophysiological functions [33]. The integrin ␣v 3 is found at low levels on mature endothelial cells and is required for maintaining vascular permeability during acute lung inflammation [34]. However, this integrin is also markedly upregulated on activated fibroblasts, tumor cells and associated vasculature [35]. Indeed this receptor is believed to help drive the differentiation of fibroblasts into endothelial cells and myofibroblasts, with increased expression described in a number of pathological conditions associated with accelerated neovascularity, such as seen in cancer, and fibrosis including different forms of organ fibrosis and cardiovascular disease. Therefore, the imaging of this receptor could be a useful biomarker for quantifying (myo)fibroblast differentiation in IPF. Fluciclatide is an arginine-glycine-aspartic acid peptide with high affinity for ␣v 3 /␣v 5 integrin (with affinities (EC50) of 11.1 and 0.1 nM respectively), which has been radiolabeled with F-18 for PET imaging of angiogenesis and active fibrosis and evaluated in a Phase 1 trial [36]. More recently published in abstract form, 18 F-fluciclatide was evaluated in a study of 5 healthy volunteers, 14 patients with systemic sclerosis related interstitial pulmonary fibrosis and 9 patients with idiopathic pulmonary fibrosis to determine its effectiveness in demonstrating areas of presumed myofibroblast differentiation [37]. 18 F-fluciclatide PET imaging was correlated with CT chest findings. The whole lungs showed nearly twice the level of 18 F-fluciclatide uptake, as quantified using the maximum standard uptake value (SUV), in the participants with lung fibrosis compared to healthy volunteers, particularly in lung areas which demonstrated higher extent of fibrosis (Fig. 3). This initial study shows the potential for this PET agent used as an imaging biomarker to identify the beginning of myofibroblast differentiation and the ultimate development of pulmonary fibrosis. 3.3. Potential for PET tracers to serve as biomarkers for treatment response PET imaging tracers can be used not only to study the relationship of specific molecular pathways to lung disease, but also to assess treatment responses after the administration of molecularly targeted therapies. As such, determining the optimal method for determining PET tracer uptake that most accurately reflects the underlying biology is necessary to move these agents forward. However, this can be challenging as obtaining direct validation of the imaging target expression in the lungs is not always possible. Many patients cannot undergo lung biopsies or bronchoalveolar lavage without significant risks to their health. Furthermore, the lungs vary in density, which alone can change the intensity of the signal in the lungs. There have been several methods proposed to account for lung density changes [38,39]; however, the most appropriate method remains to be determined. To advance the development of new PET radiopharmaceuticals, early phase studies will likely need to focus either on studying subjects who have
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Fig. 2. PET/CT images demonstrating endotoxin-induced inducible nitric oxide (iNOS) expression with 18 F(+/−)NOS. Healthy volunteers imaged before and 16 h after instillation of endotoxin in the lateral segment of the right middle lobe demonstrate increased 18 F(+/−)NOS uptake, displayed as a parametric image of the distribution volume ratio (DVR) calculated by Logan plot analysis using the pulmonary artery as the reference region. The 18 F(+/−)NOS DVR increased in all volunteers with positive iNOS immunostaining on cells obtained by bronchoalveolar lavage (BAL); however, in one volunteer in which no iNOS could be detected by immunostaining, no change in 18 F(+/−)NOS uptake was noted after endotoxin (This research was originally published in JNM, reference [32], with figure modified with permission.).
Fig. 3. 18 F-Fluciclatide PET/CT imaging of a patient with aortic stenosis and incidental pulmonary fibrosis. 18 F-Fluciclatide PET CT was being performed to evaluate for endothelial change as a cause of aortic stenosis. A. The patient also had pulmonary fibrosis, evident on the CT images in the periphery of the lungs (arrows). B. 18 F-Fluciclatide uptake corresponds to fibrotic regions (arrows) with the scale in counts. This study was performed in the Clinical Research Imaging Centre (CRIC), University of Edinburgh (courtesy of Dr S. Mirsadraee).
mild disease and thus can tolerate the risks associated with obtaining tissue or use healthy volunteer models of lung disease in which correlating tissue specimens can be more easily obtained. However, tissue sampling has recognized limitations for serving as a gold standard. Another approach will be to compare different chemical entities that bind to the same biological target or are processed
in similar ways by the same enzyme. Obtaining correlative data from these different agents could then help cross-validate all of the different agents in the absence of a gold standard [40]. These approaches, together with obtaining intrasubject reproducibility data, will be needed to validate these agents as biomarkers for assessing treatment responses. Data from patients with and with-
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out treatment over time will be required to further validate the changes in uptake of these biomarkers, in correlation with structural and functional abnormality changes using CT and/or MRI and clinical symptoms and outcomes.
4. Conclusion We are now at the beginning of a new era of research using PET imaging to study the basic pathophysiology of lung inflammation. This modality has the potential to fill an unmet need for molecularly targeted biomarkers to assess the underlying lung disease mechanisms in patients. PET tracers can serve as noninvasive, quantitative, molecularly targeted biomarkers that can be used to serve as specific treatment response markers for targeted interventions. Combining the information from PET, CT, and MRI will provide investigators with novel tools to study the relationship between the activity of specific molecular pathways that result in alterations of lung structure and function.
Conflicts of interest None of the authors have any financial conflicts to disclose for this review article.
Acknowledgement DLC is funded by the National Institutes of Health (R01 HL121218, HL116389). Role of Funding Sponsor: DLC’s research efforts which contributed to this article.
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