Acute lung injury (ALI) is one of the most frequent causes of admission to medical intensive care units. The most serious form of ALI is Acute Respiratory Distress Syndrome (ARDS) which occurs in ~200,000 patients in the U.S. per year and carries a mortality rate of 30-40%. Recent studies stress the importance of early detection of ALI for enhancing the efficacy of existing therapies and improving outcomes of ALI/ARDS patients. So important are novel means of early detection and treatment of ALI that the NHLBI has funded eleven centers to conduct clinical trials to identify and intervene early in patients at risk for ALI or ARDS. Aligned with this NHLBI priority, our long-term goal is to develop a clinical means for early detection and monitoring of ALI, including stratifying the risk of ALI development in individual patients. Single-photon emission computed tomography (SPECT) lung imaging of radiolabeled biomarkers shows unique promise as an effective tool for early detection of ALI. The utility of a given SPECT biomarker is dependent on both the sensitivity and specificity of its lung uptake to changes in a particular cellular process involved in the pathogenesis of ALI; and its early detectability prior to current clinical measures of ALI. We propose to use SPECT to probe 1) glutathione content of tissue with hexamethylpropyleneamine oxime (99mTc- HMPAO) imaging, 2) endothelial cell death with 99mTc-duramycin imaging, and 3) mitochondrial membrane potential with 99mTc-sestamibi imaging. We hypothesize that: a) in vivo lung uptake of each biomarker is sensitive and specific to a change in the activity of the cellular target, b) changes in activities of cellular targets and the lung uptake of these biomarkers precede current clinical measures of ALI, and c) biomarker imaging coupled with pharmacokinetic modeling can quantify changes in the activities of the cellular targets. Thus, the specific aims are to 1) Develop a paradigm for mechanistic and quantitative interpretation of in vivo lung biomarker image data; and 2) Characterize the in vivo lung uptake of the three biomarkers prior to clinical evidence of ALI in two rat models of human ALI/ARDS.
Under Aim 1, we propose to use a pharmacokinetic model to identify the dominant vascular and cellular processes that determine the lung uptake of each biomarker, evaluate the sensitivity and specificity of the lung uptake of each biomarker to a change in the activity of the cellular target, and estimate the activity of the cellular target from rat in vivo biomarker image data.
Under Aim 2, we propose to evaluate changes in lung uptake of the chosen biomarkers and activities of the cellular targets as indicators of early stages of hyperoxia- or lipopolysaccharide-induced ALI. The proposed research is significant because it will provide preclinical data critical to the development of a clinical means of early detection of ALI and for stratifying the risk of ALI development in individual patients. It also affords a unique opportunity to train undergraduate and graduate biomedical engineering students in biomedical imaging and methods of data acquisition and data analysis, particularly pharmacokinetic modeling.
Acute lung injury (ALI) is one of the most frequent causes of admission to the intensive care unit. The most serious form is Acute Respiratory Distress Syndrome (ARDS) which occurs in ~ 200,000 patients in the U.S. per year and carries a mortality rate of 30-40%. Recent studies stress the importance of early detection of ALI for enhancing the efficacy of existing therapies, and emphasize the need for a clinical means for early detection of ALI. The objective of this proposal is to use clinical imaging modalities and computational tools to detect and quantify changes in specific lung tissue cellular targets prior t clinical evidence of lung injury in two rat models of human ALI/ARDS. The outcomes are expected to lead to the development of a clinical means for early detection of ALI. This will have an important positive impact on ALI/ARDS patient outcomes.
