Vitamin C in Respiratory Diseases

Bovio

et al. 2011

Arzneimittelforschung

Reactive oxygen species released by activated polymorphonuclear leukocytes as an expression of their defensive function are considered to be a major source of the cytotoxic oxidant stress, that triggers a self-sustaining phlogogenic loop in the respiratory system. N-Acetylcysteine (CAS 616-91-1, NAC), a known mucolytic drug, possesses also antioxidant properties, but it undergoes a rapid and extensive first-pass metabolism resulting in low tissue availability. Thus to further improve the NAC bioavailability a single oral administration of 1200 mg NAC has been recently proposed. This study has been performed to investigate in vitro by means of luminol amplified chemiluminescence the ability of the concentration of 35 mumol/l NAC available after single oral administration of 1200 NAC to interfere with human neutrophil oxidative burst evoked by both corpuscolate and soluble stimulants, in comparison with 16 mumol/l NAC, the serum concentration obtainable after single oral administration of 600 mg NAC. At concentrations of 16 and 35 mumol/l, NAC significantly reduced in a concentration-dependent manner the activation of polymorphonuclear neutrophils (PMNs) oxidative bursts induced by all of the stimulants (C. albicans, formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate (PMA)). This effect was also present in cell-free systems, thus confirming the scavenger activity of these two concentrations of NAC. The fact that no effects were seen on PMN phagocytosis and bacterial killing indicates that NAC has no negative influence on other PMN functions such as antimicrobial activity.

Section: Abbreviationsmentioning

confidence: 99%

Human Neutrophil Oxidative Bursts and their in vitro Modulation by Different N-Acetylcysteine Concentrations

Allegra

Bovio

et al. 2011

Arzneimittelforschung

“…This is because ROS are capable of oxidizing biological molecules, such as polyunsaturated fatty acids, which leads to the lipoperoxidation of membranes, structural and enzymatic proteins, or DNA, and thus to the induction of cell damage [4−7]. As far as the respiratory system is concerned, the lungs are the only internal organs that are in direct contact with the environment and so, in addition to endogenous cell metabolism, they also have to confront the attack of ROS from exogenous xenobiotics [8]. The air we breathe frequently contains various types of biological (bacteria, viruses, pollens, etc.…”

Section: Introductionmentioning

confidence: 99%

“…Hydroxyl radicals (HO • ) can then be generated in the presence of transition metals [11]. If, for any reason, these ROS are not under control but are released in the pulmonary cell environment, they lead to epithelial, muscular, alveolar, fibroblastic and phagocytic cell injury, together with a self-sustaining phlogogenic loop [8]. For these reasons, ROS are thought to play a direct role (or be important cofactors) in a wide variety of acute/chronic disease states, such as emphysema [12−14], bronchial hyperreactivity and asthma [15− 17], cystic fibrosis [18−20], adult respiratory distress syndrome [21−23], pulmonary idiopathic fibrosis [24,25], silicosis/asbestosis [26−28], and fibrosis from xenobiotics [29−32].…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Antioxidant Activity of the SH Metabolite I of Erdosteine on Human Neutrophil Oxidative Bursts

Braga

Zuccotti

2011

Arzneimittelforschung

Acute and chronic lung diseases both lead to an extensive recruitment of neutrophils in the lungs. These cells play a major defensive role but, when activated, they are also an important source of reactive oxygen species, which generate a cytotoxic oxidant stress that triggers a self-sustaining phlogogenic loop. Erdosteine (CAS 84611-23-4) is a mucoactive drug whose metabolization leads to active metabolites with an SH group, and molecules bearing an SH group are also considered to have antioxidant activity. Luminol amplified chemiluminescence was used to investigate the oxidative bursts of human neutrophils and it was found that concentrations of 2.5, 5, 10 and 20 micrograms/ml of metabolite I of erdosteine significantly inhibit oxidative bursts in a concentration-related manner that overlaps the inhibition induced by the control drug N-acetylcysteine. Chemiluminescence was also studied in cell-free systems to see whether the drug also has direct scavenger activity, which was observed from 2.5 to 20 micrograms/ml of metabolite I using the xanthine/xanthine oxidase assay and at concentrations of 0.039 to > or = 2.5 micrograms/ml using the highly-sensitive hypochlorous acid/H2O2 assay. The findings indicate that the metabolite I of erdosteine has antioxidant activity which, together with the drug's mucomodifying activity, may lead to a useful antiphlogistic effect.

“…This function of human PMNs is of considerable interest because it may play an important role in inflammation and host defense [25] as NO can interact with the O 2 -W , produced by activated PMNs, in order to produce highly reactive species, such as peroxynitrite anions (ONOO -) [24][25][26], which are powerful oxidizing radicals that mediate some of the biological actions of NO [27]. Given the different sources of free oxidizing radicals, their molecular reactivity and the number of vital cell functions disrupted by oxidative mechanisms, they can induce a phlogogenic loop when released in the pulmonary cell environment, and this plays a direct role (or is an important cofactor) in a wide variety of acute or chronic respiratory system diseases [28][29][30].…”

mentioning

confidence: 99%

Inhibitory Effects of Metabolite I of Erdosteine on the Generation of Nitric Oxide and Peroxynitrite Chemiluminescence by Human Neutrophils

Culici²,

Bianchi³

et al. 2004

Pharmacology

Polymorphonuclear neutrophils (PMNs) can generate superoxide anions and nitric oxide (NO), which is not only an important mediator of various cellular activities, but can also react with superoxide anions to produce peroxynitrite anions (ONOO^–). Peroxynitrite is a potent and potentially toxic oxidant that damages various types of biomolecules. It preferentially mediates the oxidation of thiolic groups in protein and non-protein molecules, thus altering their functions. The aim of this study was to examine whether, in addition to its ability to reduce the respiratory bursts of human PMNs, the SH metabolite I (Met I) of erdosteine, can interfere with NO and NO-derived peroxynitrite production, thus extending its antioxidant activity. This was done by means of the luminol amplified chemiluminescence (LACL), which has been widely used to detect the production of reactive oxidant species (ROS) by PMNs under various conditions. At 5 and 10 µg/ml, Met I significantly reduced LACL after fMLP and PMA stimulation. When L-Arg was added to the reaction medium, as a NO donor, the chemiluminescence of fMLP increased by up to 67% and that of PMA by up to 132%, but was once again significantly reduced by 5 and 10 µg/ml of Met I. In a cell-free system, the use of linsidomine (SIN-1) makes it possible to investigate the behavior of LACL induced by peroxynitrite release, which was significantly reduced by Met I concentrations ranging from 1.25 to 10 µg/ml. Our findings indicate that Met I, a molecule with a SH group, reacts with ROS, NO and NO-derived peroxynitrite, and has both antioxidant and scavenging activity. This is of interest for the strategy of protecting against damage induced by radical species in the pulmonary cell environment, in which they can induce a phlogogenic loop, and suggests that adding exogenous thiols may be useful in antagonizing the toxic effects of reactive molecules on endogenous thiols.