The object of this proposal is to further develop multiple indicator dilution methods for evaluating metabolic functions of the pulmonary capillary endothelium as a means to identify and mathematically model fundamental mechanisms that affect the exchange of substrates between the blood and the endothelium in the normal and injured dog lung.
One aim of the proposed studies is to identify and evaluate factors and processes in the blood that influence the interaction of biogenic amines (serotonin and norepinephrine), prostaglandins (PGE1 and PGA1) and several synthetic substrates of angiotensin converting enzyme (ACE) with the lung endothelium. In solated dog lung lobes, cellular and protein composition of the perfusate as well as substrate-perfusate and substrate-endothelium contact time will be independently varied in order to determine quantitatively the effects of transient kinetics upon the uptake and/or metabolism of these endothelial substrates. Changes in substrate- pulmonary endothelial interactions will be quantified and analyzed using kinetic model parameters for normal lungs and compared to lungs injured by treatment with small bead embolism, high vascular pressure or several agents which alter microvascular permeability in order to test the sensitivity of the kinetic parameters to different types of lung injury. To provide an independent measure perfused surface area in the lung, an important measurement in interpreting lung metabolic functions, a second aim is directed towards evaluating the volume distribution of diazepam. Diazepam, as a lipophilic indicator, is essentially excluded from the extravascular space and thus may provide an interpretable index of changes in perfused surface area. The experiments will be conducted in the intact anesthetized dog subjected to various interventions to alter pulmonary hemodynamics, perfused surface area or extravascular water.
The third aim of the study is to develop mathematical models as concise expressions of hypotheses which account for the dominant physical, chemical, and physiological processes affecting the fate of the endothelial substrates identified above. These models will be used to quantitatively test the proposed hypotheses and to estimate kinetic parameters that could serve as quantifiers of pulmonary endothelial function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL024349-13
Application #
3337633
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1979-08-01
Project End
1995-07-31
Budget Start
1991-08-26
Budget End
1992-07-31
Support Year
13
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Marquette University
Department
Type
Schools of Engineering
DUNS #
046929621
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Ma, Dan; Wolf, Paul; Clough, Anne V et al. (2013) The performance of MLEM for dynamic imaging from simulated few-view, multi-pinhole SPECT. IEEE Trans Nucl Sci 60:
Staniszewski, Kevin; Audi, Said H; Sepehr, Reyhaneh et al. (2013) Surface fluorescence studies of tissue mitochondrial redox state in isolated perfused rat lungs. Ann Biomed Eng 41:827-36
Audi, Said H; Roerig, David L; Haworth, Steven T et al. (2012) Role of glutathione in lung retention of 99mTc-hexamethylpropyleneamine oxime in two unique rat models of hyperoxic lung injury. J Appl Physiol (1985) 113:658-65
Clough, Anne V; Audi, Said H; Haworth, Steven T et al. (2012) Differential lung uptake of 99mTc-hexamethylpropyleneamine oxime and 99mTc-duramycin in the chronic hyperoxia rat model. J Nucl Med 53:1984-91
Sepehr, Reyhaneh; Staniszewski, Kevin; Maleki, Sepideh et al. (2012) Optical imaging of tissue mitochondrial redox state in intact rat lungs in two models of pulmonary oxidative stress. J Biomed Opt 17:046010
Audi, Said; Li, Zhixin; Capacete, Joseph et al. (2012) Understanding the in vivo uptake kinetics of a phosphatidylethanolamine-binding agent (99m)Tc-Duramycin. Nucl Med Biol 39:821-5
Gan, Zhuohui; Audi, Said H; Bongard, Robert D et al. (2011) Quantifying mitochondrial and plasma membrane potentials in intact pulmonary arterial endothelial cells based on extracellular disposition of rhodamine dyes. Am J Physiol Lung Cell Mol Physiol 300:L762-72
Gan, Zhuohui; Roerig, David L; Clough, Anne V et al. (2011) Differential responses of targeted lung redox enzymes to rat exposure to 60 or 85% oxygen. J Appl Physiol 111:95-107
Ramakrishna, Madhavi; Gan, Zhuohui; Clough, Anne V et al. (2010) Distribution of capillary transit times in isolated lungs of oxygen-tolerant rats. Ann Biomed Eng 38:3449-65
Audi, Said H; Merker, Marilyn P; Krenz, Gary S et al. (2008) Coenzyme Q1 redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia. J Appl Physiol 105:1114-26

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