Despite decades of research, incidence and mortality in Acute Lung Injury (ALI) remain high, and relationships between the cellular and molecular details of ALI and their physiological manifestations remain poorly under- stood. While these details can be elucidated using small animal models, the physiological consequences are difficult to quantify, because current measures of lung function in rodents provide inadequate temporal and spatial resolution. Moreover, this methodological gap represents a substantial barrier to preclinically assessing the efficacy of ALI treatments. The long-term goal of this research is to develop an imaging modality that can quantify all spatial and temporal aspects of pulmonary function in small animal models of ALI by using a single agent-hyperpolarized (HP) 129Xe-to rapidly image pulmonary ventilation (V) and perfusion (Q). The objective of this application is to use 3D 129Xe magnetic resonance imaging (MRI) to quantitatively map the V/Q ratio in rats and measure spatial and temporal changes in the V/Q distribution following injury. The central hypothesis underlying this proposal is that MR images obtained after inhaling 129Xe and during extracorporeal (EC) infusion of 129Xe into the blood will be able to rapidly visualize the 3D, V/Q distribution. This hypothesis is based on a detailed model of HP 129Xe signal dynamics and preliminary data demonstrating 3D, 129Xe MR images that reflect V and Q. The rationale for the proposed research is that V/Q mismatching is known from clinical trials to be exceedingly important in the pathological progression of ALI. Thus, V/Q matching must be assessed to fully characterize small animal models of injury and test potential treatments. Guided by strong preliminary data, our central hypothesis will be tested by the following three Specific Aims: 1) optimize the spatial and temporal resolution of HP 129Xe V/Q MRI and establish the baseline V/Q distribution in healthy rats;2) test the ability of gas- phase 129Xe MR to follow V/Q evolution after injury in airway and vascular occlusion models;and 3) develop dissolved 129Xe MRI during EC infusion and test the ability of this technique to detect perfusion in an ALI mod- el, when hypoxic vasoconstriction is impaired. Specifically, Aim 3 will test the hypothesis that dissolved 129Xe MRI can visualize impaired hypoxic vasoconstriction after nonselective vasodilation in a saline lavage model of ALI.
Aim 1 will be conducted in the Mentored Phase (K99) of this Pathway to Independence Award, and Aim 3 will be conducted primarily in the Independent Phase (R00). The research proposed in Aim 2 will be split between the K99 and R00 phases. The proposed research is innovative in that it will enable repeated, 3D mapping of the V/Q distribution with isotropic (~1 mm) resolution in rat models of ALI within minutes, using a single agent. The proposed research is significant because it will enable previously inaccessible aspects of pathology that are known to be important in clinical ALI, namely the V/Q distribution, to be quantified in small animals. Ultimately, the methodological advances made possible by the proposed research will enable more complete validation of rodent models of ALI and establish a preclinical platform for evaluating ALI treatments.
The proposed research is relevant to public health because small animal models are necessary for studying mechanistic details in rapidly progressing human illnesses, such as ALI. These details can be better correlated with human disease if they are related quantitatively to their effects on lung physiology. Thus, this proposal is relevant to the part of NIH's mission fostering innovative research strategies that serve as a basis for protecting and improving health. It will also provide the PI with training in preclinical research and lung physiology, making him a stronger candidate for a future, independent research support, which is the goal of the K99/R00 Award.
|Cleveland, Zackary I; Virgincar, Rohan S; Qi, Yi et al. (2014) 3D MRI of impaired hyperpolarized 129Xe uptake in a rat model of pulmonary fibrosis. NMR Biomed 27:1502-14|
|Freeman, Matthew S; Cleveland, Zackary I; Qi, Yi et al. (2013) Enabling hyperpolarized (129) Xe MR spectroscopy and imaging of pulmonary gas transfer to the red blood cells in transgenic mice expressing human hemoglobin. Magn Reson Med 70:1192-9|