The adult respiratory distress syndrome is a form of acute respiratory failure often associated with gram-negative sepsis and a mortality rate exceeding 50%. Recent investigations suggest that mobilization of endogenous arachidonic acid metabolites and activation of formed blood elements, especially neutrophils, are intimately involved in the pathogenesis. In the present proposal, we will examine the role of lipoxygenase products of arachidonate metabolism in mediating endotoxin-induced acute respiratory failure in the pig. The specific objectives are: 1) to determine the effect of blocking the lipoxygenase pathway on cardiopulmonary function during infusion of E.Coli endotoxin; 2) to determine if the lipoxygenase products, leukotriene C4,eukotriene B4, and 12-HETE, are increased in bronchoalveolar lavage fluid obtained from endotoxemic pigs; 3) to determine the effect of granulocytopenia on cardiopulmonary function and production of lipoxygenase products in normal and endotoxemic pigs. Cardiopulmonary function will be evaluated for 4.5 hrs in anesthetized endotoxemic pigs. Parameters to be measured or calculated include: mean arterial, pulmonary artery, pulmonary artery wedge and airway opening pressures; crdiac output, pulmonary vascular resistance, dynamic lung compliance, lung water, arterial gas tensions and pH; hematocrit, plasma proteins, total white blood cell, polymorphonuclear, lymphocyte and platelet counts; bronchoalveolar lavage albumin and neutrophil content and postmortem ravimetric lung water. Assay for lipoxygenase metabolites will be by radioimmunoassay and high-pressure liquid chromatography. If in the proposed model, increased lipoxygenase products occur and can be correlated with abnormal cardiopulmonary function then future studies will focus on identifying specific mechanisms by which lipoxygenase products contribute to acute respiratory failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032726-02
Application #
3344177
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1985-08-01
Project End
1988-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
2
Fiscal Year
1986
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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