Pmn, eosinophils, and monocytes are inflammatory cells that possess a halide-dependent myeloperoxidase (MPO). MPO produces oxidized halides, such as hypochlorous acid/hypochlorite, which react with taurine to produce the less toxic taurine chloramine (T-Cl). Recent evidence suggests that MPO may catalyze the formation of T-Cl directly, thus bypassing formation of HOCl/OCl-. Taurine protects against tissue damage in various models of inflammation through a mechanism that is thought to involve detoxification of HOCl. However, T-Cl once formed is more than a stable inert substance; recent evidence from our laboratories suggest that T-Cl is a significant biological effector molecule. Production of NO and TNF- alpha by cultured rat alveolar macrophages and RAW 264.7 cells, a macrophage clonal cell line, is inhibited by T-Cl. Production of PGE2 may also be affected. These findings are important because NO, TNF-alpha, and PGE2 are potent inflammatory mediators that cause tissue damage in a variety of immunological events, e.g., lung damage resulting from the inflammatory response elicited by acute inhalation exposure to O3. Even though inflammatory cells contain high concentrations of taurine (intracellular), taurine supplementation protects against O3 induced lung damage. Protective effects of taurine are reported in other paradigms of inflammation as well. The primary goal of this proposal is to determine the mechanism(s) by which taurine and its active metabolite T-Cl protects against tissue damage caused by overt inflammatory responses. We will utilize in vitro cell culture models for mechanistic studies and in vivo rat models utilizing chronic and acute O3 exposures. Experiments are designed to address the following: A) Determine the formation of T-Cl under controlled in vitro conditions, B) Establish the action of T-Cl on RAW 264.7 cells and on rat alveolar macrophages activated by cytokines or by agents (BAL) that model in vivo conditions, C) Determine the molecular basis of T-Cl action on activated RAW 264.7 cells and rat alveolar macrophages regarding NO, TNF-alpha and PGE2, D) Determine the protection by taurine and T-Cl against O3 induced activation/damage in controlled in vitro studies that model in vivo conditions, and B) Determine the effects of taurine and of T-Cl on chemotaxis of human monocytes and rat pmn. Completion of these studies will not only help us to understand the mechanisms by which taurine protects against O3 induced lung injury, but may also be applicable to inflammatory responses in general.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049942-02
Application #
2392711
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1996-04-10
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Institute for Basic Research in Dev Disabil
Department
Type
DUNS #
167205090
City
Staten Island
State
NY
Country
United States
Zip Code
10314
Schuller-Levis, Georgia; Gordon, Ronald E; Wang, Chuanhua et al. (2009) Protection of bleomycin-induced fibrosis and inflammation by taurine. Int Immunopharmacol 9:971-7
Schuller-Levis, Georgia B; Park, Eunkyue (2004) Taurine and its chloramine: modulators of immunity. Neurochem Res 29:117-26
Quinn, Michael R; Liu, Yong; Barua, Madhabi et al. (2003) Taurine chloramine inhibits production of inflammatory mediators and iNOS gene expression in alveolar macrophages; a tale of two pathways: part II, IFN-gamma signaling through JAK/Stat. Adv Exp Med Biol 526:349-56
Schuller-Levis, Georgia B; Park, Eunkyue (2003) Taurine: new implications for an old amino acid. FEMS Microbiol Lett 226:195-202
Quinn, Michael R; Barua, Madhabi; Liu, Yong et al. (2003) Taurine chloramine inhibits production of inflammatory mediators and iNOS gene expression in alveolar macrophages; a tale of two pathways: part I, NF-kappaB signaling. Adv Exp Med Biol 526:341-8
Schuller-Levis, Georgia B; Gordon, Ronald E; Wang, Chuanhua et al. (2003) Taurine reduces lung inflammation and fibrosis caused by bleomycin. Adv Exp Med Biol 526:395-402
Levis, William; Schuller-Levis, Georgia B; Park, Eunkyue (2003) Deficient tumor necrosis factor-alpha production in lipoarabinomannan activated macrophages from toll-like receptor-4 deficient mice: implication for mycobacterial susceptibility. Int J Lepr Other Mycobact Dis 71:1-9
Serban, Valeria; Liu, Yong; Quinn, Michael R (2003) Production of nitric oxide by activated microglial cells is inhibited by taurine chloramine. Adv Exp Med Biol 526:357-64
Liu, Yong; Barua, Madhabi; Serban, Valeria et al. (2003) Production of inflammatory mediators by activated C6 cells is attenuated by taurine chloramine inhibition of NF-kappaB activation. Adv Exp Med Biol 526:365-72
Liu, Yong; Quinn, Michael R (2002) Chemokine production by rat alveolar macrophages is inhibited by taurine chloramine. Immunol Lett 80:27-32

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