The adult respiratory distress syndrome (ARDS) is a form of acute respiratory failure (ARF) often associated with gram-negative sepsis and a mortality rate of 50% or higher. Recent observation suggest that toxic 02 metabolites and mobilization of arachidonic acid metabolites are intimately involved in the pathogenesis. Infusion of endotoxin into animals is considered an excellent model of ARDS because many features of the syndrome can be reproduced. We propose to examine the roles of lipoxygenase and cyclooxygenase products, and their interaction with toxic 02 metabolites, in the pathophysiology of endotoxin-induced ARF. These objectives will be accomplished by utilizing an isolated perfused porcine lung (IPPL) in addition to the in vivo animal model. The specific objectives are: 1) To determine the role of lipoxygenase products during endotoxemia in the intact and during endotoxin treatment of the IPPL preparation by specific blockade of the lipoxygenase pathway (BW A46) and LTD4/LTE4 receptors (LY171883), and by infusion of leukotrienes into isolated lungs. 2) To determine the role of cyclooxygenase products by specific blockade of cyclooxygenase (indomethacin) and thromboxane synthetase (dazoxiben) pathways, thromboxane A2 (TXA2) receptors (SQ 29,548), and by infusion of a TXA2 mimetic (U46619) into lungs pretreated with endotoxin and a cyclooxygenase inhibitor. 3) To determine the role of toxic 02 metabolites during endotoxemia and their interaction with eicosanoid biosynthesis in vivo and in the IPPL. This will be accomplished by treating intact and isolated pig lungs with scavengers of hydrogen peroxide (polyethylene glycol catalase and hydroxyl radical (dimethylthiourea). LTB4, LTC4/LTD4/LTE4, 12- HETE, and 15-HETE will be measured using reverse phase-high performance liquid chromatography ultraviolet spectroscopy, and radioimmunoassay. TXB2 and 6-keto-PGFI will also be measured by radioimmunoassay. Physiologic parameters to be measured or calculated include: pulmonary vascular and airway pressures, pulmonary vascular resistance, lung vascular endothelial and alveolar-capillary membrane permeability, lung water, PO2, PCO2, and alveolar dead-space ventilation. If increased levels of eicosanoids can be correlated with the presence of toxic 02 metabolites and abnormal cardiopulmonary function, then future studies will focus on identifying specific cellular mechanisms by which these metabolites contribute to lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032726-08
Application #
3344182
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1985-08-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1994-07-31
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
North Carolina State University Raleigh
Department
Type
Schools of Veterinary Medicine
DUNS #
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Kruse-Elliott, K T; Whorton, A R; Olson, N C (1998) Role of lipid-derived mediators in tumor necrosis factor-induced endothelin-1 release in vivo. Shock 9:40-5
Dodam, J R; Adler, K B; Olson, N C (1996) Effect of pertussis toxin and B-oligomer on platelet-activating factor-induced generation of inositol phosphates in porcine alveolar macrophages. Am J Vet Res 57:574-9
Dodam, J R; Olson, N C (1995) Effect of fluoride on cardiopulmonary function and release of eicosanoids in pigs. J Appl Physiol 78:569-77
Olson, N C; Hellyer, P W; Dodam, J R (1995) Mediators and vascular effects in response to endotoxin. Br Vet J 151:489-522
Dodam, J R; Olson, N C; Friedman, M (1994) Differential effects of tumor necrosis factor-alpha and platelet-activating factor on bovine pulmonary artery endothelial cells in vitro. Exp Lung Res 20:131-41
Kruse-Elliott, K T; Olson, N C (1993) CGS 8515 and indomethacin attenuate cytokine-induced cardiopulmonary dysfunction in pigs. Am J Physiol 264:H1076-86
Kruse-Elliott, K T; Pino, M V; Olson, N C (1993) Effect of PAF receptor antagonism on cardiopulmonary alterations during coinfusion of TNF-alpha and IL-1 alpha in pigs. Am J Physiol 264:L175-82
Olson, N C; Kruse-Elliott, K T; Whorton, A R et al. (1993) Pertussis toxin attenuates platelet-activating factor-induced pulmonary hemodynamic alterations in pigs. Am J Physiol 264:L213-21
Olson, N C; Kruse-Elliott, K T; Johnson, L W (1993) Effect of 5-lipoxygenase and cyclooxygenase blockade on porcine hemodynamics during continuous infusion of platelet-activating factor. Prostaglandins Leukot Essent Fatty Acids 49:549-59
Olson, N C; Kruse-Elliott, K T; Dodam, J R (1992) Systemic and pulmonary reactions in swine with endotoxemia and gram-negative bacteremia. J Am Vet Med Assoc 200:1870-84

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