Metabolic Imaging and Biological Assessment: Platforms to Evaluate Acute Lung Injury and Inflammation

Mehrdad Pourfathi, Stephen J Kadlecek, Shampa Chatterjee, Rahim R Rizi, Mehrdad Pourfathi, Stephen J Kadlecek, Shampa Chatterjee, Rahim R Rizi

Abstract

Pulmonary inflammation is a hallmark of several pulmonary disorders including acute lung injury and acute respiratory distress syndrome. Moreover, it has been shown that patients with hyperinflammatory phenotype have a significantly higher mortality rate. Despite this, current therapeutic approaches focus on managing the injury rather than subsiding the inflammatory burden of the lung. This is because of the lack of appropriate non-invasive biomarkers that can be used clinically to assess pulmonary inflammation. In this review, we discuss two metabolic imaging tools that can be used to non-invasively assess lung inflammation. The first method, Positron Emission Tomography (PET), is widely used in clinical oncology and quantifies flux in metabolic pathways by measuring uptake of a radiolabeled molecule into the cells. The second method, hyperpolarized 13C MRI, is an emerging tool that interrogates the branching points of the metabolic pathways to quantify the fate of metabolites. We discuss the differences and similarities between these techniques and discuss their clinical applications.

Keywords: ARDS; FDG-PET; HP-MRI; lung inflammation; lung injury.

Copyright © 2020 Pourfathi, Kadlecek, Chatterjee and Rizi.

Figures

FIGURE 1
FIGURE 1
Radiographic and Computed Tomographic (CT) Findings in the Acute, or Exudative, Phase (Panels A,C) and the Fibrosing-Alveolitis Phase (Panels B,D) of Acute Lung Injury and the Acute Respiratory Distress Syndrome (ARDS). Panel (A) shows a chest radiograph from a patient with the ARDS associated with gram-negative sepsis who was receiving mechanical ventilation. There are diffuse bilateral alveolar opacities consistent with the presence of pulmonary edema. Panel (B) shows an anteroposterior chest radiograph from another patient with ARDS who had been receiving mechanical ventilation for seven days. Reticular opacities are present throughout both lung fields, a finding suggestive of the development of fibrosing alveolitis. Panel (C) shows a CT scan of the chest obtained during the acute phase. The bilateral alveolar opacities are denser in the dependent, posterior lung zones, with sparing of the anterior lung fields. The arrows indicate thickened interlobular septa, consistent with the presence of pulmonary edema. Panel (D) shows a CT scan of the chest obtained during the fibrosing-alveolitis phase. There are reticular opacities and diffuse ground-glass opacities throughout both lung fields, and a large bulla is present in the left anterior hemithorax. Reproduced with permission from Ware and Matthay (2000).
FIGURE 2
FIGURE 2
Etiologies, manifestations and sequelae of ARDS/ALI. Upon diagnosis, patients undergo supportive therapy using protective ventilation. The patient’s overall condition is assessed by chest radiography, computed tomography, ventilatory parameters and ABG. Treatment either results in resolution of ARDS/ALI or in the syndrome’s progression into severe respiratory failure, pulmonary fibrosis and eventual multi-organ failure. Reproduced with permission from Pourfathi (2019).
FIGURE 3
FIGURE 3
The healthy lung (left), and the acute phase of ARDS/ALI (right). In ARDS/ALI, injury is initiated by either direct or indirect insults to the delicate alveolar structure of the distal lung and associated micro-vasculature. In the acute phase of the injury, resident alveolar macrophages are activated, leading to the release of potent pro-inflammatory mediators and chemokines that promote the accumulation of neutrophils and monocytes. Reproduced with permission from Ware and Matthay (2000).
FIGURE 4
FIGURE 4
(A) Lung lactate production measured by the difference in the lactate concentration across the lungs (arteriovenous difference in lactate) in various groups of patients shows that lungs of ALI patients produce significant amounts of lactate. (B) Lung lactate production measured in 43 patients with acute injury showed that it is proportional to injury severity as determined by Murray’s lung injury score (Murray et al., 1988). (ALI, acute lung injury; CPE, acute pulmonary edema; BPN, bronchopneumonia; LTx, lung transplantation; Other, other types of respiratory failure, mEq/min.M2: mmoles per minute per square meter). Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society from De Backer et al. (1997). The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. *p < 0.05 versus ALI, +p < 0.01 versus ALI.
FIGURE 5
FIGURE 5
Representative axial computed tomography (CT) in the middle panel, and coronal (left) and axial (right) [18F] fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) at the obtained from 4 patients, 72 hours after diagnosis with acute lung injury. Moderate uptake of FDG was observed in non/poorly aerated regions (black arrows). In contrast, uptake of FDG was low in normally aerated lung (white arrow). Reproduced with permission from Rodrigues et al. (2008).
FIGURE 6
FIGURE 6
(Top) Metabolites and their biochemical pathways that can be interrogated using [1-13C] pyruvate. MRI. The red circle indicates atoms with 13C labeled nuclei. The fate of the pyruvate beyond Acetyl-CoA into the Tricarboxylic Acid (TCA) cycle cannot be probed using [1-13C] pyruvate as the 13C labeled nucleolus remains on the 13CO2 molecule. Cofactors are not shown in this diagram for simplicity (LDH, lactate dehydrogenase; ALT, alanine transaminase; PDH, pyruvate dehydrogenase; CA, carbonic anhydrase). (Bottom) (A) NMR spectrum obtained from a mouse after administration of hyperpolarized [1-13C] pyruvate via the tail-vein. (B) Spectra obtained every second shows how different peaks vary over time. (C) Area under each peak depicted as a function of time to represent the relative concentration of each peak. Reproduced with permission from Pourfathi (2019).
FIGURE 7
FIGURE 7
(A) Pyruvate, lactate and lactate -to-pyruvate segmented maps overlaid on their corresponding proton image of a ZEEP rat 4 h after the acid instillation shows injury to the posterior right lung marked by increased intensity in the proton image (white arrow). The metabolite maps show increased lactate signal intensity and lactate-to-pyruvate ratio colocalized with the injured area. (B) Hematoxylin and Eosin (H&E) axial slide of the whole lung clearly shows damaged lung tissue in the same area (black arrow). Magnified images taken from the injured area (black box) with (C) 10× and (D) 40× magnifications show severe damage and inflammatory infiltrates in the tissue. The bar in (C) is 100 μm. Reproduced with permission from Pourfathi (2019).

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