We perceive that aggregating agents fall into 3 categories: 1) agents which transiently aggregate neutrophils (PMN) (e.g., C5a and synthetic oligopeptides [FMLP]), cause equally transient neutropenia and evanescent mild lung dysfunction; 2) agents which transiently aggregate PMN and platelets (PL) (e.g., platelet activating factor [PAF]) cause equally transient neutropenia and thrombocytopenia and severe lung dysfunction; 3) agents which aggregate PMN and PL irreversibly (e.g., phorbol myristate acetate [PMA]) cause prolonged (greater than 3 hr) neutropenia, thrombocytopenia, and lung dysfunction. We propose that C5a, FMLP, PAF, BUT NOT PMA are active in vivo because they trigger the generation of arachidonate metabolites which mediate cytopenias and lung dysfunction. We will test this hypothesis by measuring blood levels of two arachidonate metabolites (e.g. PGE2 and TXB2), following intravenous administration of the various stimuli; by assessing the effects of arachidonate antimetabolites on the in vivo actions of C5a, FMLP, PAF, and PMA; by determining if PMN of PL obtained from treated rabbits are insensitive (i.e., are desensitized) to stimulation by C5a, FMLP, PAF, LTB4, or PMA; by determining if certain arachidonate metabolites can mimic the actions of the stimuli; and, where possible, by determining if these bioactive arachidonate metabolites circulate in the blood of treated rabbits. In addition, we will explore the role of endogenous C5a, PAF, and arachidonate metabolism on the syndrome of endotoxin shock, a syndrome that also involves neutropenia, thrombocytopenia, and lung dysfunction. In these pursuits our aim is to find evidence supporting the hypothesis that various endogenously formed aggregating agents (e.g., products of arachidonate metabolism or PAF) mediate various syndromes which associate cytopenia with lung dysfunction. Finally, we will examine the effects of these mediators on lung function and structure when administered to animals over prolonged periods (i.e., days to months). These studies may uncover possible etiologies for acute or chronic lung disease and fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029293-05
Application #
3340392
Study Section
Pathology A Study Section (PTHA)
Project Start
1982-09-01
Project End
1987-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
5
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
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Yoza, B K; Hu, J Y; Cousart, S L et al. (2000) Endotoxin inducible transcription is repressed in endotoxin tolerant cells. Shock 13:236-43
Learn, C A; Mizel, S B; McCall, C E (2000) mRNA and protein stability regulate the differential expression of pro- and anti-inflammatory genes in endotoxin-tolerant THP-1 cells. J Biol Chem 275:12185-93
Delong, P; O'Sullivan, M G; Huggins, E et al. (1999) Bacterial lipopolysaccharide induction of the prostaglandin G/H synthase 2 gene causes thromboxane-dependent pulmonary hypertension in rabbits. Am J Respir Cell Mol Biol 20:493-9
Yoza, B; LaRue, K; McCall, C (1998) Molecular mechanisms responsible for endotoxin tolerance. Prog Clin Biol Res 397:209-15
Yoza, B K; Wells, J D; McCall, C E (1998) Interleukin-1beta expression after inhibition of protein phosphatases in endotoxin-tolerant cells. Clin Diagn Lab Immunol 5:281-7
Fasano, M B; Wells, J D; McCall, C E (1998) Human neutrophils express the prostaglandin G/H synthase 2 gene when stimulated with bacterial lipopolysaccharide. Clin Immunol Immunopathol 87:304-8
Yoza, B K; Hu, J Y; McCall, C E (1996) Protein-tyrosine kinase activation is required for lipopolysaccharide induction of interleukin 1beta and NFkappaB activation, but not NFkappaB nuclear translocation. J Biol Chem 271:18306-9
McCall, C E; Grosso-Wilmoth, L M; LaRue, K et al. (1993) Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome. J Clin Invest 91:853-61
O'Sullivan, M G; Huggins Jr, E M; McCall, C E (1993) Lipopolysaccharide-induced expression of prostaglandin H synthase-2 in alveolar macrophages is inhibited by dexamethasone but not by aspirin. Biochem Biophys Res Commun 191:1294-300

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