Inflammatory Effects on Pmn Metabolites of Linoleic Acid

Shasby, Douglas Michael

Abstract

This laboratory has a long standing interest in mechanisms of acute inflammatory edema. Investigations by this group and others have identified important roles for PMN derived oxidants, proteases and cationic proteins in mediating acute inflammatory edema. In this proposal the investigators will extend prior observations about the edemagenic activity of fatty acids oxidized by PMN through an aspirin sensitive pathway. The specific questions that will be asked are: 1. What are the oxymetabolites of linoleic acid exposed to human PMN separated from blood? Which of the metabolites' production is inhibited by aspirin? What is the role of platelets in production of the metabolites? 2. Do stimulated PMN metabolize endothelial cell linoleate to the same oxymetabolites? 3. Do the aspirin sensitive PMN-oxymetabolites of linoleic acid increase the permeability of endothelial and epithelial cell monolayers in vitro, are they cytolytic to endothelial and epithelial cells, and do they initiate phospholipid hydrolysis in endothelial and epithelial cells? 4. What are the effects of the PMN-oxymetabolites of linoleic acid on endothelial and epithelial cell membrane ionic conductances? 5. In what PMN cellular fraction is the aspirin sensitive oxidase and is it distinct from cyclooxygenase?

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Heart, Lung, and Blood Institute (NHLBI)
• Type: Specialized Center (P50)
• Project #: 5P50HL037121-10
• Application #: 5213622
• Support Year: 10
• Fiscal Year: 1996

Publications

Yarovinsky, Timur O; Monick, Martha M; Hunninghake, Gary W (2003) Integrin receptors are crucial for the restimulation of activated T lymphocytes. Am J Respir Cell Mol Biol 28:607-15

Yarovinsky, T O; Hunninghake, G W (2001) Lung fibroblasts inhibit activation-induced death of T cells through PGE(2)-dependent mechanisms. Am J Physiol Lung Cell Mol Physiol 281:L1248-56

Chen, W; Hunninghake, G W (2000) Effects of ragweed and Th-2 cytokines on the secretion of IL-8 in human airway epithelial cells. Exp Lung Res 26:229-39

Geist, L J; Powers, L S; Monick, M M et al. (2000) Asbestos stimulation triggers differential cytokine release from human monocytes and alveolar macrophages. Exp Lung Res 26:41-56

Monick, M M; Carter, A B; Gudmundsson, G et al. (1999) A phosphatidylcholine-specific phospholipase C regulates activation of p42/44 mitogen-activated protein kinases in lipopolysaccharide-stimulated human alveolar macrophages. J Immunol 162:3005-12

Gudmundsson, G; Hunninghake, G W (1999) Respiratory epithelial cells release interleukin-8 in response to a thermophilic bacteria that causes hypersensitivity pneumonitis. Exp Lung Res 25:217-28

Carter, A B; Monick, M M; Hunninghake, G W (1999) Both Erk and p38 kinases are necessary for cytokine gene transcription. Am J Respir Cell Mol Biol 20:751-8

Monick, M M; Carter, A B; Hunninghake, G W (1999) Human alveolar macrophages are markedly deficient in REF-1 and AP-1 DNA binding activity. J Biol Chem 274:18075-80

Gudmundsson, G; Monick, M M; Hunninghake, G W (1999) Viral infection modulates expression of hypersensitivity pneumonitis. J Immunol 162:7397-401

Goebel, E A; Davidson, B L; Graham, S M et al. (1998) Tumor reduction in vivo after adenoviral mediated gene transfer of the herpes simplex virus thymidine kinase gene and ganciclovir treatment in human head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 119:331-6