During the last decade, growing evidence has shown that serum gamma-glutamyl transpeptidase (GGT) is an independent prognostic marker for cardiac death and reinfarction, both in unselected populations and in patients with coronary artery disease. Clinical and epidemiological evidence indicates that the prognostic value of GGT is largely independent of other risk factors for cardiovascular disease and alcohol consumption. The catalytic activity of GGT, which is present on the surface of cell membranes and in serum, is responsible for the extracellular catabolism of the antioxidant glutathione. Cysteinyl glycine deriving from the hydrolysis of glutathione performed by GGT has been found to trigger iron-dependent production of reactive oxygen species as well as low-density lipoprotein oxidation in vitro. The localization of GGT within the coronary plaque ( Figure) provides a pathological basis for the hypothesis of a direct participation of GGT in low-density lipoprotein oxidation within the plaque and in atherogenesis and coronary artery disease progression.From the Department of Experimental Pathology, University of Pisa, Pisa (A. Paolicchi, A. Pompella); the Institute of Clinical Physiology, National Research Council, Pisa (M.E., C.P.); Azienda Ospedaliera Pisana, Pisa (E.C.); and Clinica Villa Maria Beatrice, Firenze (E.G., G.P.), Italy.Correspondence Histochemical and immunohistochemical demonstration of GGT enzyme activity within a frozen section of coronary atheroma from endoarteriectomy in vivo. Histochemical reaction for GGT enzyme activity was performed by using the specific substrate gamma-glutamyl-4-methoxy-2-naphtylamide and the diazonium salt Fast Garnet GBC as a chromogen. A strong GGT activity (the red stain) is selectively present in correspondence of the core of the atheroma, while the fibrous cap stains negative (A, magnification 20ϫ). The identification of the enzyme was confirmed immunohistochemically using a polyclonal antibody directed against the heavy chain of human GGT, which marked the same part of the atheroma (B and C, magnification 40ϫ and 10ϫ, respectively). The homogeneous immunostaining of oxidized lipid-containing foam cells by the antibody is evident at higher magnification (B). For the sake of confirming the localization of GGT activity, another section of the same specimen was immunostained with an antibody directed against CD 68ϩ cells (ie, macrophages), selectively identifying foam cells (D and E, magnification 10ϫ and 40ϫ, respectively).
Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
The results obtained suggest the presence in plaques of a serum-like GGT protein, indicating that a direct contribution of serum GGT to enzyme activity found within atherosclerotic lesions is possible. Data also indicate the occurrence of GGT-mediated redox reactions within plaque environment, which might influence plaque progression.
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