The long-term objective is to examine the possible role of the macrophage in asthma. The focus will be on the lipoxygenase pathway of arachidonic acid metabolism in this cell because of convincing evidence that the products of this pathway are important mediators in asthma and airway hyperresponsiveness.
The specific aims will be to characterize the lipoxygenase products of human mononuclear phagocytes, including macrophages and monocytes, in the lung and examine the relationship of stimulation and activation of these cells to bronchoconstriction and airway hyperresponsiveness. The strategy of the project will be to characterize the lipoxygenase pathway of human homonuclear phagocytes isolated from the lung and the blood and to evaluate the effects of stimulation and in vitro conditioning on their lipoxygenase products. Lipid biochemical analysis will be performed using the techniques of chromatography and spectroscopy as well as other techniques for lipid analysis. The relevance of the findings in the biochemical studies to asthma will be initially evaluated by examining the physiologic significance of macrophage stimulation and activation on airway tone and responsiveness, in animals. In the future, parallel studies in human subjects may be possible to directly evaluate the relevance of the findings to asthma. The research may provide further understanding of the role of the macrophage in airway disease and will also lead to further insight into the biology of the mononuclear phagocyte in the lung. Because studies in human cells will be directly relevant to human disease, these investigations may suggest specific therapeutic approaches to airway disease mediated through the macrophage and its lipoxygenase pathway.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Research Manpower Review Committee (MR)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Ring, W L; Riddick, C A; Baker, J R et al. (1997) Activated lymphocytes increase expression of 5-lipoxygenase and its activating protein in THP-1 cells. Am J Physiol 273:C2057-64
Ring, W L; Riddick, C A; Baker, J R et al. (1996) Human monocytes lose 5-lipoxygenase and FLAP as they mature into monocyte-derived macrophages in vitro. Am J Physiol 271:C372-7
Ring, W L; Riddick, C A; Baker, J R et al. (1996) Lymphocytes stimulate expression of 5-lipoxygenase and its activating protein in monocytes in vitro via granulocyte macrophage colony-stimulating factor and interleukin 3. J Clin Invest 97:1293-301
Shindo, K; Baker, J R; Munafo, D A et al. (1994) Captopril inhibits neutrophil synthesis of leukotriene B4 in vitro and in vivo. J Immunol 153:5750-9
Bigby, T D; Lee, D M; Minami, M et al. (1994) Characterization of human airway epithelial cell leukotriene A4 hydrolase. Am J Respir Cell Mol Biol 11:615-24
Munafo, D A; Shindo, K; Baker, J R et al. (1994) Leukotriene A4 hydrolase in human bronchoalveolar lavage fluid. J Clin Invest 93:1042-50
Bigby, T D (1991) Transcellular metabolism of leukotrienes in the lung. Adv Exp Med Biol 314:235-50
Bigby, T D; Lee, D M; Meslier, N et al. (1989) Leukotriene A4 hydrolase activity of human airway epithelial cells. Biochem Biophys Res Commun 164:1-7
Bigby, T D; Meslier, N (1989) Transcellular lipoxygenase metabolism between monocytes and platelets. J Immunol 143:1948-54
Tamaoki, J; Sekizawa, K; Ueki, I F et al. (1987) Effect of macrophage stimulation on parasympathetic airway contraction in dogs. Eur J Pharmacol 138:421-5