Dietary glycine blunts lung inflammatory cell influx following acute endotoxin

Abstract

Mortality associated with endotoxin shock is likely mediated by Kupffer cells, alveolar macrophages, and circulating neutrophils. Acute dietary glycine prevents mortality and blunts increases in serum tumor necrosis factor-alpha (TNF-alpha) following endotoxin in rats. Furthermore, acute glycine blunts activation of Kupffer cells, alveolar macrophages, and neutrophils by activating a glycine-gated chloride channel. However, in neuronal tissue, glycine rapidly downregulates chloride channel function. Therefore, the long-term effects of a glycine-containing diet on survival following endotoxin shock were investigated. Dietary glycine for 4 wk improved survival after endotoxin but did not improve liver pathology, decrease serum alanine transaminase, or effect TNF-alpha levels compared with animals fed control diet. Interestingly, dietary glycine largely prevented inflammation and injury in the lung following endotoxin. Surprisingly, Kupffer cells from animals fed glycine for 4 wk were no longer inactivated by glycine in vitro; however, isolated alveolar macrophages and neutrophils from the same animals were sensitive to glycine. These data are consistent with the hypothesis that glycine downregulates chloride channels on Kupffer cells but not on alveolar macrophages or neutrophils. Importantly, glycine diet for 4 wk protected against lung inflammation due to endotoxin. Chronic glycine improves survival by unknown mechanisms, but reduction of lung inflammation is likely involved.

Dietary glycine blunts liver injury after bile duct ligation in rats

“…Oxidative stress and activation of Kupffer cells are probably involved in the pathogenesis of liver injury caused by cholestasis. Glycine has been shown to be an anti-inflammatory amino acid acting via inhibitory effects on several white blood cells, including Kupffer cells [15][16][17][18][19] . Glycine activates a chloride channel, leading to cell hyperpolarization and a concomitant blocking of calcium influx via a voltage dependent calcium channel [20] .…”

“…T he underlying mechanisms are not completely understood. Glycine decreases oxidative stress [15][16][17][18][19] by different and partly indirect mechanisms that prevent reactive oxygen species formation. Furthermore, glycine protects renal tubular cells, hepatocytes and endothelial cells against injury from hypoxia, ischemia-reperfusion and ATP depletion [16,[36][37][38][39] .…”

“…The glycine receptor exists in a wide variety of cells, beside its typical occurrence at the postsynaptic neuronal membranes of the spinal cord. Besides endothelial cells and renal proximal tubular cells [17,41] , cells involved in inflammatory and immune responses, such as macrophages, monocytes, neutrophils, and T lymphocytes, express a glycine receptor [18,20,[42][43][44] . Glycine acts thru its receptor on inflammatory cells, such as Kupffer cells, to suppress activation of transcription factors and the formation of free radicals and inflammatory cytokines.…”

“…Glycine, a simple nonessential amino acid, is a well-known inhibitory neurotransmitter in the central nervous system that acts via a glycine-gated chloride channel and has been shown to be protective against hypoxia, ischemia, and various cytotoxic substances [15][16][17] . Furthermore, it was demonstrated that dietary glycine protected both, the lung and the liver against lethal doses of endotoxin in the rat [18] and improved graft survival after liver transplantation [19] . Based on pharmacological data [15][16][17] , a glycine-gated chloride channel was detected in Kupffer cells and other macrophages [20] that influenced the activation process of these cells.…”

Dietary Glycine Inhibits Angiogenesis During Wound Healing and Tumor Growth

“…This results in decreased production of oxygen free radicals from inflammatory cells (primarily macrophages) and effectively blunts their function. 3 It is mainly through this mechanism that dietary glycine has been shown to protect against LPS induced endotoxic shock 4 and arthritis, 5 accelerate recovery after alcohol induced liver injury, 6 attenuate CCl4 induced fibrosis, 7 improve survival after liver transplantation 8 and decrease toxicity of certain drugs. 9 Angiogenesis is a complex process through which new blood vessels are formed from the existing vasculature.…”