The purpose of this proposal is to generate new and useful information on the role of products of lipoxygenase-mediated arachidonic acid metabolism as endogenous mediators of edema formation in acute lung injury (ALI). It was demonstrated previously in an animal model of ALI produced by intravenous ethchlorvynol (ECV) administration that cyclooxygenase metabolites influence the development of systemic hypoxemia, but not the accumulation of extravascular lung water (EVLW). In this model a product of lipoxygenase activity, leukotriene C4 (LTC4) was present in increased amounts in edema fluid and bronchopulmonary lavage fluid (BALF). In preliminary studies in which ALI was produced by phorbol myristate acetate (PMA), LTC4 and LTD4 were found to be increased in BALF. These studies, coupled with the finding that LTC4 was increased in humans with the adult respiratory distress syndrome, suggest that LTC4 and LTD4, two edemagenic products of lipoxygenase metabolism, may play a role in the edema of ALI.
The Specific Aims of this proposal are: 1) to demonstrate that increased production of LTC4 and LTD4 is a feature common to two dissimilar models of ALI; 2) to establish that the increased production of LTC4 and LTD4 occurs in and is confined to the injured ling; 3) to demonstrate that increased production of LTC4 and LTD4 is specific for ALI, i.e., LTC4 and LTD4 are not produced in association with hydrostatic pulmonary edema; 4) to establish that products of cyclooxygenase activity are not responsible for the edema of ECV- and PMA-induced ALI; and 5) to establish that LTC4 and LTD4 contribute to the formation of nonhydrostatic pulmonary edema in these models of ALI. Experiments will be performed in which either unilateral or bilateral ALI is produced in dogs. Concentrations of LTC4 and LTD4 will be determined in blood, edema fluid, BALF and lung slice incubation medium. Attempts will be made to correlate the concentrations of LTC4 and LTD4 to the extent of edema formation. The role of LTC4 and LTD4 as factors contributing directly to edema formation will be investigated through the use of synthesis inhibitors and a leukotriene receptor antagonist. Successful completion of these studies will make the mechanisms of edema formation more comprehensible to the basic scientist and will permit the clinician to formulate more rational therapeutic approaches to the clinical condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001867-02
Application #
3082267
Study Section
(SRC)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Sprague, R S; Stephenson, A H; Joshi, S N et al. (1994) Effect of indomethacin on increases in leukotriene B4 and pulmonary edema in response to phorbol ester administration in dogs. Biochem Pharmacol 48:1009-15
Sprague, R S; Stephenson, A H; Dimmitt, R A et al. (1994) Inhibition of nitric oxide synthesis results in a selective increase in arterial resistance in rabbit lungs. Pol J Pharmacol 46:579-85
Wurtz, M M; Stephenson, A H; Sprague, R S et al. (1992) Enhanced microvascular permeability of PMA-induced acute lung injury is not mediated by cyclooxygenase products. J Appl Physiol 73:2135-41
Sprague, R S; Stephenson, A H; Lonigro, A J (1992) OKY-046 prevents increases in LTB4 and pulmonary edema in phorbol ester-induced lung injury in dogs. J Appl Physiol 73:2493-8
Sprague, R S; Thiemermann, C; Vane, J R (1992) Endogenous endothelium-derived relaxing factor opposes hypoxic pulmonary vasoconstriction and supports blood flow to hypoxic alveoli in anesthetized rabbits. Proc Natl Acad Sci U S A 89:8711-5
Sprague, R S; Stephenson, A H; Dahms, T E et al. (1990) Production of leukotrienes in phorbol ester-induced acute lung injury. Prostaglandins 39:439-50
Stephenson, A H; Sprague, R S; Dahms, T E et al. (1990) Thromboxane does not mediate pulmonary hypertension in phorbol ester-induced acute lung injury in dogs. J Appl Physiol 69:345-52
Sprague, R S; Stephenson, A H; Dahms, T E et al. (1989) Proposed role for leukotrienes in the pathophysiology of multiple systems organ failure. Crit Care Clin 5:315-29