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.
Showing the most recent 10 out of 20 publications
