There are five specific aims: 1) We will attempt to detect and localize oxidized alpha 1-proteinase inhibitor in lung biopsies obtained from smoking and sham-smoking baboons. For this purpose, a specific monoclonal antibody that recognizes only the oxidized inhibitor will be used as the primary staining reagent, followed by established secondary-antibody immunohistochemical methods (peroxidase-antiperoxidase, avidin-biotin). This objective is important to human health because oxidation of alpha 1- proteinase inhibitor in the lungs by cigarette smoking has been implicated as a major pathogenetic factor in pulmonary emphysema, but remains unproven. 2) We will explore the role of a newly discovered mast cell elastase in the pathogenesis of smokers' emphysema in three ways: (a) by monitoring release of the enzyme (using ELISA-techniques) from purified human lung mast cells incubated with aqueous solutions of tobacco smoke and smoke fractions; (b) by measuring levels of histamine (a marker of mast cell secretory response) in bronchoalveolar lavage fluids of human smokers (before and after smoking) and of rats following acute exposure to inhaled cigarette smoke; and (c) by attempting to induce experimental emphysema in rats and dogs using repeated intrapulmonary instillations of mast cell secretogogues. 3) We will attempt to develop new inhibitors of human neutrophil elastase (a protease suspected on being a pathogenetic factor in pulmonary emphysema) based on our recent characterization of a specific neutrophil elastase inhibitor in pneumococci. 4) We will test an oxidation-resistant, genetically-engineered, mutant (Met 358Val) alpha 1-proteinase inhibitor for its resistance to inactivation in vivo in an established animal model of acute cigarette smoke exposure. 5) Finally, we will measure levels o f the neutrophil-monocyte marker antigen (L1) in blood and airspace secretions of septic and traumatized patients at risk for adult respiratory distress syndrome (ARDS) and in those with frank ARDS. Levels of the L1 protein may prove to have predictive value of ARDS in high-risk subjects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL014262-19
Application #
3334754
Study Section
Pathology A Study Section (PTHA)
Project Start
1976-12-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
19
Fiscal Year
1990
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Ying, Q L; Kemme, M; Simon, S R (1994) Functions of the N-terminal domain of secretory leukoprotease inhibitor. Biochemistry 33:5445-50
Liao, G; Simon, S R (1994) Temporal down-regulation of Fc gamma RIII expression and Fc gamma receptor-mediated phagocytosis in human monocyte-derived macrophages induced by TNF-alpha and IL-1 beta. J Leukoc Biol 55:702-10
Tyagi, S C; Simon, S R; Carter, C A (1994) Effect of pH and nonphysiological salt concentrations on human immunodeficiency virus-1 protease dimerization. Biochem Cell Biol 72:175-81
Liao, G; Simone, J; Simon, S R (1994) Paracrine downregulation of Fc gamma RIII in human monocyte-derived macrophages induced by phagocytosis of nonopsonized particles. Blood 83:2294-304
Mallya, S K; Hall, J E; Lee, H M et al. (1994) Interaction of matrix metalloproteinases with serine protease inhibitors. New potential roles for matrix metalloproteinase inhibitors. Ann N Y Acad Sci 732:303-14
Tyagi, S C; Simon, S R (1994) Elastin-derived peptide binding to a hydrophobic domain on neutrophil elastase. Biochem Cell Biol 72:419-27
Ying, Q L; Simon, S R (1993) Kinetics of the inhibition of human leukocyte elastase by elafin, a 6-kilodalton elastase-specific inhibitor from human skin. Biochemistry 32:1866-74
Sorsa, T; Lindy, O; Konttinen, Y T et al. (1993) Doxycycline in the protection of serum alpha-1-antitrypsin from human neutrophil collagenase and gelatinase. Antimicrob Agents Chemother 37:592-4
Tyagi, S C; Simon, S R (1993) Regulation of neutrophil elastase activity by elastin-derived peptide. J Biol Chem 268:16513-8
Sorsa, T; Konttinen, Y T; Lindy, O et al. (1993) Doxycycline protects serum alpha-1-antitrypsin from human neutrophil collagenase. Agents Actions Suppl 39:225-9

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