This program proposes to stdy the pathogenesis of acute respiratory failure following pulmonary vascular injury. We hypothesize that acute respiratory failure due to vascular injury (ARDS; non-cardiac pulmonary edema) occurs because of lung edema, loss of hypoxic pulmonary vasoconstriction and abnormal airway function. We hyupothesize that all of those changes, regardless of the etiology, are mediated by metabolites of archidonic acid (and perhaps other related fatty acids) and granulocytes. We propose to test these hypotheses by 1) detailed stdies of effects of arachidonic acid (and related fatty acids) and their metabolites on lung function, 2) detailed studies of the interaction of granulocytes with the lung circulation, the pathophysiological effects of pulmonary leukostasis and themechanisms of those effects, 3) theoretical and experimental studies of transvascular transport which will define the contributions of pressures, flows, exchanging vessel surface area and vascular permeability to lung fluid balance, 4) studies of the pathogenesis of lung abnormalities in four animal models of human disease-gram negative endotoxemia, pulmonary oxygen toxicity, neurogenic pulmonary edema, and acute myocardial infarction, and 5) studies of the pathogenesis of lung abnormalities in humans with cardiogenic and noncardiogenic pulmonary edema and the therapeutic effects of high dose methylprednisolone in patients with the adult respiratory distress syndrome. Most of the animal studies will be done in chronically instrumented unanesthetized sheep prepared for collection of lung lymph; multiple indicator dilution measurements of lung water and permeability will be used in humans and animals. Measurements of prostaglandins, thromboxanes, arachidonate lipoxygenase products and in vitro chemotaxis assays as well as body plethysmographic measurements of lung mechanics, will also be important to the studies. Investigators in Medicine, Bioengineering, Pharmacology, Surgery and Pediatrics will participate in the program. The studies will help to define the pathogenesis of lung failure following vascular injury, enhance our understanding of physical factors affecting lung fluid following vascular injury, enhance our understanding of physical factors affecting lung fluid balance, provide a rational basis for designing therapies for patients with pulmonary edema (cardiogenic or ARDS) and critically evaluate the effects of methylprednisolone in humans with ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL019153-09
Application #
3106542
Study Section
(SRC)
Project Start
1976-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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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