Pulmonary granulomatous hypersensitivity reactions (e.g., to invasive parasites) may cause a dramatic stimulation of eosinophil production and local accumulation but eosinophil functions in these reactions are unknown. It has been suggested that these cells may assist in the cytotoxic destruction of the parasite or alternatively that they may be homeostatic cells and serve to suppress the vigorous inflammatory reaction and minimize unnecessary damage to host tissues. This investigation will define the roles of eosinophils in such responses through the following approaches: 1) Examine destruction of newborn and muscle stage trichinella larvae in vitro: Morphologic study of development of pulmonary, peritoneal, or subcutaneous granulomata around larvae administered intravenously, intraperitoneally, or subcutaneously. Determine distribution of inflammatory cells within granulomata, in particular specific cells interacting directly with larvae. Examine timing, sequence, and site of activation of eosinophil lysosomal enzymes and subsequent degranulation by EM cytochemistry. Recover larvae from granulomata to determine kinetics of larval destruction as judged by morphology, motility, infectivity, and ability to incorporate 3H-2-deoxyglucose. 2) Examine cytotoxic reactions of controlled mixtures of purified effector cells (eosinophils, neutrophils, macrophages, lymphocytes; with and without antibody and complement) against trichinella larvae in vitro. Examine cytotoxic ability of purified human eosinophils and neutrophils obtained from normal and chronic granulomatous disease patients. 3) Develop models of parasite destruction employing target cells (mastocytoma cells, fibroblasts) coated with trichinella antigens. Examine cytotoxicity of effector cells against antigen-coated target cells. 4) Examine whether eosinophils amplify or suppress lymphocyte and macrophage cytotoxicity in the in vitro models. 5) Determine whether effects observed with intact cells can be duplicated using eosinophil lysosomal enzymes alone or with hydrogen peroxide and halide in a manner designed to mimic the eosinophil oxidative metabolic response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI014929-08
Application #
3125932
Study Section
(EH)
Project Start
1979-09-01
Project End
1987-11-30
Budget Start
1986-09-01
Budget End
1987-11-30
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Bauldry, S A; Nasrallah, V N; Bass, D A (1992) Activation of NADPH oxidase in human neutrophils permeabilized with Staphylococcus aureus alpha-toxin. A lower Km when the enzyme is activated in situ. J Biol Chem 267:323-30
Bauldry, S A; Elsey, K L; Bass, D A (1992) Activation of NADPH oxidase and phospholipase D in permeabilized human neutrophils. Correlation between oxidase activation and phosphatidic acid production. J Biol Chem 267:25141-52
Agwu, D E; McPhail, L C; Sozzani, S et al. (1991) Phosphatidic acid as a second messenger in human polymorphonuclear leukocytes. Effects on activation of NADPH oxidase. J Clin Invest 88:531-9
Bauldry, S A; Wykle, R L; Bass, D A (1991) Differential actions of diacyl- and alkylacylglycerols in priming phospholipase A2, 5-lipoxygenase and acetyltransferase activation in human neutrophils. Biochim Biophys Acta 1084:178-84
Bauldry, S A; Bass, D A; Cousart, S L et al. (1991) Tumor necrosis factor alpha priming of phospholipase D in human neutrophils. Correlation between phosphatidic acid production and superoxide generation. J Biol Chem 266:4173-9
Nieto, M L; Venable, M E; Bauldry, S A et al. (1991) Evidence that hydrolysis of ethanolamine plasmalogens triggers synthesis of platelet-activating factor via a transacylation reaction. J Biol Chem 266:18699-706
Bauldry, S A; McCall, C E; Cousart, S L et al. (1991) Tumor necrosis factor-alpha priming of phospholipase A2 activation in human neutrophils. An alternative mechanism of priming. J Immunol 146:1277-85
Wheeler, J G; Winkler, L S; Seeds, M et al. (1990) Influenza A virus alters structural and biochemical functions of the neutrophil cytoskeleton. J Leukoc Biol 47:332-43
Bauldry, S A; Wykle, R L; Bass, D A (1988) Phospholipase A2 activation in human neutrophils. Differential actions of diacylglycerols and alkylacylglycerols in priming cells for stimulation by N-formyl-Met-Leu-Phe. J Biol Chem 263:16787-95
Bass, D A; McPhail, L C; Schmitt, J D et al. (1988) Selective priming of rate and duration of the respiratory burst of neutrophils by 1,2-diacyl and 1-O-alkyl-2-acyl diglycerides. Possible relation to effects on protein kinase C. J Biol Chem 263:19610-7

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