We hypothesize that important characteristics of the lung vascular barrier can be measured by multiple indicator methods based on small molecules which passively cross the capillary barrier, are taken up by the endothelium or react with free radicals generated in the microcirculation during lung injury. To test this hypothesis, we will compare 14C-urea permeability surface area (PS) and other transport parameters to quantities derived from the extraction of flow limited tracers (3H-water), tracers which are both hydrophilic and lipophilic (14C- butanediol), tracers which are taken up by the endothelium (3H- norepinephrine) and tracers which react with free radicals (dimethylsulfoxide). We will examine the abilities of these substances (alone or by comparison to urea PS, CO diffusing capacity and lymph flow and protein content) to measure capillary surface area effects, to quantify lung vascular damage, to measure flow and flow distribution effects and to quantitate free radical production in the living lung. Experiments will be performed in isolated, perfused and ventilated dog lungs, the in situ perfused sheep lung with lymph cannulation in intact sheep. Lung vascular surface and flow distribution will be altered by flow variation, lung mass removal, glass bead injection, vasoconstriction and vasodilation with pharmacological agents. Lung injury will be generated by alloxan infusion in dog lungs and by perilla ketone and E. coli endotoxin infusion in sheep lungs. The results will be analyzed with the goal of improving understanding of the interplay of hemodynamic and transport factors in normal and injured lung and of developing practical methods for characterizing microvascular transport in the lungs of intact animals and patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
2P50HL019153-16
Application #
3843873
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Brigham, K L; Lane, K B; Meyrick, B et al. (2000) Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsin-deficient subjects: comparison with protein therapy. Hum Gene Ther 11:1023-32
Conner, B D; Bernard, G R (2000) Acute respiratory distress syndrome. Potential pharmacologic interventions. Clin Chest Med 21:563-87
Mangialardi, R J; Martin, G S; Bernard, G R et al. (2000) Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 28:3137-45
Brigham, K L; Stecenko, A A (2000) Gene therapy for acute lung injury. Intensive Care Med 26 Suppl 1:S119-23
Arons, M M; Wheeler, A P; Bernard, G R et al. (1999) Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 27:699-707
Peters, M T; Brigham, K L; King, G A et al. (1999) Optimization of cationic liposome-mediated gene transfer to human bronchial epithelial cells expressing wild-type or abnormal cystic fibrosis transmembrane conductance regulator (CFTR). Exp Lung Res 25:183-97
Wheeler, A P; Bernard, G R (1999) Treating patients with severe sepsis. N Engl J Med 340:207-14
Snapper, J R; Trochtenberg, D S; Hwang, Y S et al. (1999) Effect of pulmonary edema on tracheal diameter. Respiration 66:522-7
Dupont, W D; Plummer Jr, W D (1998) Power and sample size calculations for studies involving linear regression. Control Clin Trials 19:589-601
Clark, M P; Chow, C W; Rinaldo, J E et al. (1998) Multiple domains for initiator binding proteins TFII-I and YY-1 are present in the initiator and upstream regions of the rat XDH/XO TATA-less promoter. Nucleic Acids Res 26:2813-20

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