Human phagocytes play a pivotal role in mediating tissue damage in a variety of inflammatory disease states. In order to gain insights into the pathogenesis of tissue injury during inflammation, our attention will focus on the ability of two populations of human phagocytes, the neutrophil and monocyte, to generate and utilize a group of highly reactive chlorinated, oxygen metabolites. We will examine the abililty of physiologically relevant, immune stimuli to trigger the phagocytes to generate and utilize the chlorinated oxidants in a number of in vitro model systems specifically chosen to mimic in vivo inflammatory processes. Emphasis will be placed on two types of cell-derived oxidants, a short-lived specied with characteristics similar if not identical to hypochlorous acid and a newly described, long-lived oxidant with properties identical to those of N-chloroamines. Based on the known chemical characteristics of these oxidants, their biological impact will be assessed in separate but parallel in vitro systems. Specifically we will 1) examine and quantitate the ability of immune triggered phagocytes to generate hypochlorous acid, 2) determine the ability of the intact phagocyte to utilize this oxidant to mediate extracellular cytotoxicity, 3) study the biochemical features of hypochlorous acid dependent damage and 4) assess the ability of target cells to regulate their sensitivity to oxidant attack by the chlorinated oxidant. In the other portions of this study we will determine the ability of phagocytes to generate endogenous N-chloramines and examine the factors controlling their production. Finally, we will carefully evaluate the chemical reactivity of the N-chloroamines in order to provide rational guidelines for predicting their ability to interact with inflammatory mediators and target cell populations. Taken together, these studies will provide new information into the pathogenesis of inflammation at the cellular and molecular level and should allow us to plan rationale therapeutic interventions aimed at attenuating tissue destruction in disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021301-02
Application #
3131263
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Filippov, Sergey; Caras, Ingrid; Murray, Richard et al. (2003) Matrilysin-dependent elastolysis by human macrophages. J Exp Med 198:925-35
Punturieri, A; Filippov, S; Allen, E et al. (2000) Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J Exp Med 192:789-99
Rice, W G; Weiss, S J (1990) Regulation of proteolysis at the neutrophil-substrate interface by secretory leukoprotease inhibitor. Science 249:178-81
Weiss, S J (1989) Tissue destruction by neutrophils. N Engl J Med 320:365-76
Kanofsky, J R; Hoogland, H; Wever, R et al. (1988) Singlet oxygen production by human eosinophils. J Biol Chem 263:9692-6
Weiss, S J (1986) Oxygen, ischemia and inflammation. Acta Physiol Scand Suppl 548:9-37
Test, S T; Weiss, S J (1986) Assay of the extracellular hydrogen peroxide pool generated by phagocytes. Methods Enzymol 132:401-6
Weiss, S J; Test, S T; Eckmann, C M et al. (1986) Brominating oxidants generated by human eosinophils. Science 234:200-3
Peppin, G J; Weiss, S J (1986) Activation of the endogenous metalloproteinase, gelatinase, by triggered human neutrophils. Proc Natl Acad Sci U S A 83:4322-6
Weiss, S J; Peppin, G; Ortiz, X et al. (1985) Oxidative autoactivation of latent collagenase by human neutrophils. Science 227:747-9