As a fundamental bodily response to insult, inflammation is at the root of a multitude of serious lung disorders. Research using hyperpolarized gas magnetic resonance imaging (HP gas MRI), computed tomography (CT), and other imaging techniques has developed parameters for the assessment of the structural and functional alterations correlated with pulmonary inflammation. However, these approaches are unable to assess the metabolic changes that precede and underlie these alterations. In light of this knowledge gap, the proposed research seeks to optimize the carbon-13 MR approach to metabolic imaging and synthesize it with structural and functional data in order to improve the clinical management of pulmonary inflammation. Carbon-13 MR has significant promise as a metabolic imaging modality due to its ability to detect the different energy needs of inflamed lung. But its potential has been limited by a lack of hyperpolarized bio-probes other than pyruvate. The first stage of our research thus proposes to implement a technique for converting hyperpolarized pyruvate into hyperpolarized bicarbonate, carbon dioxide, and acetate. These novel probes will support the development of new biochemical markers of regional lung inflammation. Here, we will utilize hyperpolarized bicarbonate and carbon dioxide to carry out non-invasive, regional pH mapping in animal lungs. Optimization of this method will allow us to sensitively detect the acidification associated with many inflammatory pulmonary diseases before they alter lung structure and function. Because of inflammation's ubiquity in lung disorders, these techniques could be used to investigate a number of different clinical problems. In the research proposed here, we will tackle a specific longstanding clinical issue: the management of mechanical ventilation in patients with lung injury. These patients often develop ventilator-induced lung injury (VILI), a propagation and worsening of pulmonary inflammation. There exists no widely accepted protocol for the calibration of ventilator settings in order to limt the spread of inflammation, as the relationship between structural and functional data and various ventilator approaches is nebulous. In applying carbon-13 MR to this problem, we hope to develop a more direct and sensitive means of assessing inflammatory progression in order to devise appropriate ventilator strategies. The highly interdisciplinary nature of this research-it contains elements of physics, chemistry, radiology, pulmonology, and anesthesiology-make its findings potentially impactful for a diverse population of scientists and clinicians. The particula techniques we develop here can be used to investigate many inflammatory lung disorders, including asthma, COPD, and cystic fibrosis. More broadly, the availability of new hyperpolarized substrates will facilitate metabolic imaging research on several other organs, including the brain, heart, kidney, and liver.

Public Health Relevance

This project uses hyperpolarized carbon-13 magnetic resonance imaging (MRI) in combination with functional and structural imaging techniques as a new strategy for the investigation of pulmonary inflammation. Inflammation is at the root of many serious disorders including acute lung injury, COPD, and asthma. Carbon-13 MRI is capable of obtaining regional data on the molecular and cellular alterations that accompany inflammation. Such fine-grained information will allow scientists and clinicians to better understand this inflammation, detect it at an earlier stage, and more sensitively assess how it responds to treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL124986-03
Application #
9210117
Study Section
Special Emphasis Panel (ZRG1-SBIB-Z (03)M)
Program Officer
Punturieri, Antonello
Project Start
2015-02-06
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$725,795
Indirect Cost
$249,221
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cereda, Maurizio; Xin, Yi; Hamedani, Hooman et al. (2017) Tidal changes on CT and progression of ARDS. Thorax 72:981-989
Pourfathi, Mehrdad; Xin, Yi; Kadlecek, Stephen J et al. (2017) In vivo imaging of the progression of acute lung injury using hyperpolarized [1-13 C] pyruvate. Magn Reson Med 78:2106-2115
Drachman, Nicholas; Kadlecek, Stephen; Pourfathi, Mehrdad et al. (2016) In vivo pH mapping of injured lungs using hyperpolarized [1-(13) C]pyruvate. Magn Reson Med :
Cereda, Maurizio; Xin, Yi; Meeder, Natalie et al. (2016) Visualizing the Propagation of Acute Lung Injury. Anesthesiology 124:121-31
Cereda, Maurizio; Xin, Yi; Hamedani, Hooman et al. (2016) Mild loss of lung aeration augments stretch in healthy lung regions. J Appl Physiol (1985) 120:444-54