Abstract

This proposal examines the role of lipid mediators (platelet activating factor (PAF) and eicosanoids including cyclooxygenase, lipoxygenase and monooxygenase products of arachidonic acid) in endotoxin-induced pulmonary dysfunction. Special attention is given to the alterations in lung mechanics and airway responsiveness caused by endotoxin.
The Specific Aims are: 1. To determine the direct and secondary effects of purified lipid mediators on lung function in vivo and on cells and lung tissue in vitro. 2. To determine the quantity, timing and pattern of release of lipid mediators following endotoxin exposure in vivo and in vitro. 3. To determine the effects of receptor antagonists and inhibitors of PAF and eicosanoid metabolism on endotoxin-induced lipid mediator release and pulmonary dysfunction in chronically instrumented awake sheep. State-of-the-art analytic methods and a natural skepticism about the specificity of pharmacologic probes are used to carefully define the roles of individual mediators and interactions, if any, among lipid mediators in endotoxin-induced pulmonary dysfunction. It is the long-term objective of this proposal to gain understanding that will assist in the development of interventions relevant to the prevention or treatment of the adult respiratory distress syndrome (ARDS) and asthma in man.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL027274-07A2
Application #
3339036
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1981-04-01
Project End
1993-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203

  Publications

Snapper, J R; Trochtenberg, D S; Hwang, Y S et al. (1999) Effect of pulmonary edema on tracheal diameter. Respiration 66:522-7
Snapper, J R; Thabes, J S; Lefferts, P L et al. (1998) Role of endothelin in endotoxin-induced sustained pulmonary hypertension in sheep. Am J Respir Crit Care Med 157:81-8
Snapper, J R; Lefferts, P L; Lu, W et al. (1998) Effect of cardiogenic and noncardiogenic pulmonary edema on histamine responsiveness in sheep. J Appl Physiol 85:1635-42
Snapper, J R; Lu, W; Lefferts, P L et al. (1998) Effect of platelet-activating factor-receptor antagonism on endotoxin-induced lung dysfunction in sheep. J Appl Physiol 84:1610-4
Snapper, J R; Lu, W; Lefferts, P L et al. (1997) Cyclooxygenase products contribute to endothelin-induced pulmonary hypertension and altered lung mechanics in sheep. Pulm Pharmacol Ther 10:111-8
Zeldin, D C; Plitman, J D; Kobayashi, J et al. (1995) The rabbit pulmonary cytochrome P450 arachidonic acid metabolic pathway: characterization and significance. J Clin Invest 95:2150-60
Conary, J T; Parker, R E; Christman, B W et al. (1994) Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene. J Clin Invest 93:1834-40
Christman, B W; Christman, J W; Dworski, R et al. (1993) Prostaglandin E2 limits arachidonic acid availability and inhibits leukotriene B4 synthesis in rat alveolar macrophages by a nonphospholipase A2 mechanism. J Immunol 151:2096-104
Ishihara, Y; Sheller, J (1993) Effect of leukotrienes on sheep airway smooth muscle. J Lipid Mediat 7:47-56
Kuratomi, Y; Lefferts, P L; Christman, B W et al. (1993) Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep. J Appl Physiol 74:596-605

Showing the most recent 10 out of 47 publications