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Role of N-Acetylcysteine in the treatment of Acute Respiratory Disorders 3. Inflammatory Process Many mechanisms are involved in the inflammatory process including mediators, gene expression, oxidative stress and free radicals. [7,10-12] Oxidative stress, an important part of the inflammatory response to both environmental and internal signals, results from the production of oxygen-free radicals and other oxidant agents. Endogenous and exogenous oxidants (any molecule with an unpaired electron on its outer orbit) are capable of injuring the lung. [10,13] Free radicals are highly reactive molecules that can either donate (reduce) or abstract (oxidize) an electron to other nearby molecules. These reactive species also activate transcription factors, leading to the release of proinflammatory cytokines and thus an increase in the inflammatory response. [7,14] Therefore, it appears that oxidative stress and inflammation are inseparable phenomena (figure 3). Oxidative stress is responsible for alterations in many components of the lungs, including the airway wall, alveolar epithelial cell layer, lung matrix, pulmonary microcirculation and transcription factors. [14] Oxidative stress causes an amplified inflammatory response, lipid peroxidation and cell membrane damage, which results in acute inflammation, increased mucous secretion and tissue damage (figure 3). In turn, each of these results in clinical effects, such as difficult expectoration and risk of infection, cough, bronchoconstriction, and decline in lung function. In addition to initiating inflammation, cell and tissue injury caused by oxidative stress maintains inflammation. [12] Antioxidants neutralize free radicals and restore the reductive-oxidative (redox) balance and, therefore, reduce the damage to cells and DNA caused by free radicals. [10,13] 3.1 Role of Cigarette Smoke and Air Pollution Oxidants are produced by cells in the human body, but cigarette smoke and atmospheric pollution are also a source (figure 4). [7,10,13,15,16] Free radicals and potent catalyzers of oxidation reactions (e.g. iron and other Fig. 3 Role of oxidative stress and free radicals in acute inflammation. Oxidative stress Oxygen-free and nitrogen-free radicals produced Lipid peroxidation Cell membrane damage Modified cellular redox equilibrium Release of proinflammatory cytokines Inflammation of airways and lung 5
Current <strong>Therapeutics</strong> transition metals) are present in large amounts in cigarette smoke, leading to oxidative stress and airway inflammation. Smokers have greater levels of some systemic inflammatory markers than nonsmokers. Air-borne pollutants (e.g. from fossil fuel combustion products, diesel exhaust particles and residual oil fly ash) contribute to respiratory illness in urban and industrial areas. [7] Particulate air pollution has proinflammatory activities (e.g. release of inflammatory markers and generation of free radicals) similar to those seen with cigarette smoke. The lung can be protected by: [10,13,16,17] • reducing the oxidant burden (e.g. limiting exposure to cigarette smoke or air-borne pollutants) • increasing antioxidant defenses by increasing normal antioxidants (e.g. enzymes [superoxide dismutases, catalase, glutathione peroxidase] and vitamins E and C) or by administering exogenous antioxidants, such as NAC, that have well established antioxidant properties. Fig. 4 Role of cigarette smoke and atmospheric pollution on oxidative stress and inflammation in airways and lung. Inhaled by individual Oxygen- and nitrogen-free radicals and other highly reactive compounds Oxidative stress Acute inflammation of airways and lungs Cigarette smoke Air-borne pollution (e.g. particulate air pollution, ozone, heavy metals) 6
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