Oxidative Damage of Biological Molecules

Exposure to exogenous sources of ROS such as cigarette smoke, air pollutants, or endogenously released ROS from leukocytes and macrophages involved in the inflammatory process can induce oxidative stress and the oxidant/antioxidant imbalance (Figure 2) [15]. Neutrophils have a key role in inflammatory processes and have been implicated in the development and progression of all of the pulmonary features of COPD through the release of destructive mediators such as neutrophil elastase and matrix metalloproteinases. Moreover, pulmonary neutrophilic inflammation is a feature of cigarette smoking, but importantly, in patients with COPD, it is sustained even following smoking cessation [27, 28]. Activated immune cells such as neutrophils and macrophages release ROS as a part of the inflammatory process [29]. ROS can react with biological molecules such as lipid, protein, DNA, RNA, and mitochondrial DNA and leads to epithelial cell injury and death (Figure 3), which con- tribute to COPD development.
During the respiratory burst, neutrophil myeloperoxidase catalyzes the oxidation of chloride ions (Cl−) by hydrogen per- oxide (H2O2) to generate the anionic ROS hypochlorite (OCl-) or its conjugate acid, hypochlorous acid (HOCl) (Figure 4(a)) [27]. The concentration of HOCl in the interstitial fluids of inflamed tissue has been estimated to reach more than 5 mM. HOCl has high reactivity, rapidly reacts with a variety of biomolecules, and cannot reach distant intracellular targets [30]. However, reaction of HOCl with amines can generate much more stable chloramines that can diffuse greater dis- tances [27]. Only a few low molecular weight amines, such as nicotine in cigarette smoke, have been found to form chlo- ramines that can cross cellular membranes and mediate HOCl-induced intracellular protein damage [31].
At the molecular level, ROS may induce lipid peroxidation (Figure 4(b)) and yield products such as malondialdehyde, which has the ability to inactivate many cellular proteins by generating protein cross-linkages [32]. This may stimulate pulmonary inflammation [33], promoting alveolar wall destruction and emphysema development. Another product of lipid peroxidation is 4-hydroxy-2,3-nonenal, which has many cytotoxic effects [34]. It has been shown to cause cyto- plasmic Ca2+ accumulation, induce expression of proinflam- matory cytokines and NF-κB, mitochondrial dysfunction, and apoptosis. The end products of lipid peroxidation such as ethane, pentane, and 8-isoprostane are elevated in the breath and serum of patients with COPD [35].
ROS can also cause reversible and irreversible protein modifications. Protein s-sulfenation, s-nitrosylation, s-glu- tathionylation, disulfides, thiosulfinates, sulfenamides, sulfi- namides, and persulfides are reversible modifications [36, 37]. They are involved in redox regulation of protein func- tions by ROS and RNS. Moreover, these modifications play

FigurE 2: Exogenous and endogenous sources of ROS such as superoxide anions, hydrogen peroxide, hydroxyl radicals, and hypochlorous acid in cells.

Biological effects of ROS

FigurE 3: ROS reaction with various biomolecules such as proteins, lipids, and DNA may cause cell injury leading to apoptosis and necrosis.

H2O2 + Cl− → OCl− + H2O

Q• + QH2 → 2H+ + 2Q•− Q•− + O2 → Q + O •−
O •− + 2H+ → H O

RH + •OH → H2O + R• R• + O2 → ROO•
ROO• + RH → ROOH + R•

O •− + NO• → ONOO−


FigurE 4: The mechanism of ROS interaction with biomolecules. (a) Hypochlorite anion production catalyzed by myeloperoxidase; (b) lipid peroxidation; (c) production of hydrogen peroxide; (d) peroxynitrite generation; (e) production of alkyl peroxynitrites. H2O2—hydrogen peroxide; −OCl—hypochlorite anion; RH—unsaturated lipid; •OH—hydroxyl radical; R•—lipid radical; ROO•—lipid peroxyl radical; ROOH—lipid peroxide; Q/QH2—quinone/hydroquinone; O •−—superoxide anion; NO•—nitric oxide; ONOO−—peroxynitrite;
ROONO—alkyl peroxynitrites.

important roles in health because they contribute to regulation of cellular defense systems and protection against oxidative stress. Protein carbonyls, nitrotyrosines, sulfinic acids, sulfonic acids, and sulfonamides are irreversible modifications [37, 38]. Oxidation of proteins may lead to activation of NF-κB, p38 MAPK, induction of inflammatory genes, and inhibition of the activity of endogenous antiproteases, which may contribute to this disease pathogenesis [39]. Although, irreversibly oxidized proteins are often indicators of high oxidative stress and oxidative damage and are detected in lung diseases, they may also be present under normal conditions.
Moreover, ROS can also induce RNA, DNA, and mitochondrial DNA (mtDNA) damage. Studies suggest that RNA is more vulnerable to oxidative damage than other cellular

components [40]. RNA could have enhanced susceptibility for oxidative attack because of its widespread cytosolic distribution, single-stranded structure, absence of protective histones, and lack of an advanced repair mechanism [41]. More than 20 different types of base damage by hydroxyl radicals have been identified [40].
The most prevalent oxidized base in RNA is 8- hydroxy guanosine (8-OHG). The highly reactive hydroxyl radical first reacts with guanine to form a C8-OH adduct radical. Then, the loss of an electron and proton generates 8-OHG (an oxidized RNA nucleoside). It is worth to notice that RNA oxidation is more prevalent than DNA oxidation in alveolar wall cells in emphysema [41]. How- ever, DNA oxidation promotes microsatellite instability, inhibits methylation, and accelerates telomere shortening.

8-hydroxy-2′-deoxyguanosine (8-OHdG) is a product of oxidized DNA and widely used as a marker of oxidative cellular damage. Moreover, p53 mutation, observed in lung cancer, is linked to a direct DNA damage due to exposure to carcinogens in cigarette smoke [42]. It is worth noting that patients with emphysema have a high risk of lung cancer development [43]. ROS are also the main source of mt DNA damage and mutagenesis [44]. The main products of mt DNA base damage are thymine glycol among pyrimidines and 8-OHdG among purines. The former has low mutagenicity, whereas the latter upon replication can cause characteristic G→T transversions. Mt DNA with
oxidative damage may lead to mitochondrial dysfunction

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