Quantitative magnetic resonance imaging of pulmonaryperfusion

Project Summary/Abstract The goal of this project is to establish a pharmacokinetic model for absolute quantification of pulmonary perfusion and microvascular parameters and validate this model in large animal models with independent tissue analyses of perfusion, vascular permeability, and pathological features. Idiopathic pulmonary fibrosis (IPF) is a

progressive and ultimately fatal disease with highly variable clinical courses and poorly understood pathogenic mechanisms. Accumulating evidence shows that abnormalities in the pulmonary endothelium set off a cascade of events that promote increased vascular permeability, fibroblast activation, and excessive extracellular matrix

deposition, ultimately leading to the development of fibrotic lung tissue and impaired lung function. However, the changes in the pulmonary endothelium of the fibrotic lung have not been well defined. Dynamic contrast- enhanced MRI (DCE-MRI) is a powerful imaging technique whereby the kinetics of an intravenous contrast bolus

such as the FDA-approved agent Gd-DOTA can be modeled for quantitative measurement of tissue perfusion and vascular permeability. Accurate assessment of these changes in IPF will provide an improved understanding of the pathophysiology of pulmonary fibrosis, which is valuable for improving patient care and

facilitating drug development for this deadly disease. Previously, we demonstrated that DCE-MRI with model- free analysis allows for indirect but sensitive detection of alterations in perfusion, permeability, or extracellular extravascular volume in patients with IPF or prior COVID infection compared to healthy volunteers, thus providing

in vivo regional functional information not otherwise available. However, the pathophysiological interpretation of these results remains to be elucidated because the model-free approach indirectly measures a collective effect of changes in perfusion and microvascular parameters. The standard pharmacokinetic model in common use

for DCE-MRI, Tofts model, is oversimplified, assuming instantaneous intercompartmental water exchange and negligible blood volume which are not valid for the lung and thus propagates into significant systematic errors in physiological parameters extracted from DCE data. To overcome these challenges, I propose to extend the

standard Tofts model to encompass intercompartmental water exchange rate and true compartmental fractions for DCE-MRI of the lung and validate the physiological measurements derived from this extended model with independent tissue analyses in a large animal model of IPF. The output of this project will be a robust analytical

tool for absolute quantification of pulmonary perfusion and microvascular parameters in the lung, which will not only provide a quantitative understanding of the pathophysiologic mechanism underlying IPF and other pulmonary diseases but also be valuable for improving patient care and facilitating drug development for this

deadly disease.