The objectives of this program are to develop the experimental and theoretical basis for non-destructive evaluation of the metabolic status of the lung. This renewal application is based on the premise that information about the redox status of the lung cells is important for evaluating the lung response to physiological and pathophysiological stresses, and that two classes of redox active compounds will be particularly useful as multiple indicator dilution, MID, probes for obtaining this information: 1) cell impermeant electron acceptors that are reduced at the capillary endothelial surface on passage through the lungs, and 2) cell permeant electron donors that, during passage through the lungs, enter the lung tissue wherein they can be oxidized by various mechanisms. The changes in physical-chemical properties that accompany the changes in the redox state of these probes affects their optical properties, making the oxidized and reduced forms distinguishable, and their propensity for passing through cell membranes, altering the time course for their passage through the lungs.
The Specific Aims are to 1) determine what information about lung metabolic function is contained in the venous effluent concentration versus time data obtained following passage of these probes through the lungs, and 2) determine whether probe reduction and/or oxidation within the lung are modified by conditions that alter the redox status of lung cells to the extent that the information contained in the data can be used to evaluate the redox status of the lung tissue. The general approach will be to measure the pulmonary disposition of a group of indicator probes chosen from these two classes, along with some additional indicators for other relevant aspects of lung tissue and vascular function. Lungs will be treated with metabolic inhibitors and oxygen radical scavengers, chosen to help identify the mechanisms involved in probe disposition. Initial studies will be carried out using isolated rat lungs, wherein certain important variables can be manipulated to advantage. These studies will include lungs from normal rats and from rats exposed to stresses known or suspected to affect lung redox status (e.g., hyperoxia, hypoxia, and lipopolysaccharide treatment). Mathematical models will be developed that provide a means for evaluating hypotheses regarding probe disposition and for estimating parameters that can reveal the extent to which a process contributes to a change in probe disposition when lung biology has been altered. Finally, the experimental and model development will be applied to studies in anesthetized rabbits exposed to similar stresses to evaluate in vivo applicability.
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