Original contributionInhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant 1
Introduction
Chronic bronchial inflammation is a process involved in the pathogenesis of many inflammatory diseases, such as asthma, acute respiratory disease, and chronic obstructive pulmonary disease (COPD). The pathology of chronic bronchitis includes airway mucus gland hyperplasia, mucus hypersecretion, and an influx of inflammatory cells including neutrophils, macrophages, and lymphocytes [1], [2], [3], [4], [5]. In addition, airway epithelium may undergo other changes leading to squamous cell metaplasia. Chronic inflammation may also provide the ideal environment for cellular changes that lead to cancer. The molecular mechanisms of airway inflammation in COPD or in lung cancer are as yet undetermined.
It is well established that cigarette smoke causes squamous cell metaplasia in humans [6], [7]. The sequence of events leading to squamous cell metaplasia in humans remains unknown. In most cases of squamous cell metaplasia, an accompanying increase in inflammatory cells is observed that may result in the release of mitogens or modifiers of differentiation that act on the neighboring epithelium. Indeed, inflammation is often observed with squamous cell metaplasia in individuals with chronic lung conditions, including bronchopulmonary dysplasia or bronchiectasis [8], [9]. Polosukhin has proposed a possible pathway for the transformation that the bronchial epithelium undergoes during chronic inflammation: from an initial hyperplastic state (hyperplasia of goblet cells or basal epithelial cells) through a proliferative transitory phase toward altered differentiation (squamous metaplasia or atrophy) [10].
One potential mechanism of increased airway inflammation is the formation of free radicals leading to oxidative stress and increased production of proinflammatory molecules, including macrophage inflammatory protein-2 (MIP-2) and intercellular adhesion molecule-1 (ICAM-1) [11]. The gas-phase of cigarette smoke contains more than 1014 low-molecular-weight carbon- and oxygen-centered radicals per puff [12], [13]. In addition, nitric oxide (NO) is present in smoke at up to 500 ppm [14]. Radicals, in the form of semiquinones, are found in the tar-phase of smoke [13], [15], [16]. While these semiquinone radicals are relatively stable, they can reduce oxygen to produce superoxide, hydrogen peroxide, and hydroxyl radical. In addition, inhaled cigarette smoke increases the recruitment and activation of phagocytes resulting in further production of reactive oxygen species (ROS) by inflammatory cells [17], [18]. Numerous investigations have highlighted and emphasized ROS production and inflammation in smokers and individuals with COPD [19], [20], [21].
A number of enzymes are involved in protection against the injurious effects of ROS. These enzymes include superoxide dismutase (SOD), catalase, and glutathione peroxidase. In addition to these enzymes, antioxidants such as glutathione, ascorbate, α-tocopherol, uric acid, and lipoic acid also protect against oxidants. Overexpression of SOD and catalase has been shown to provide protection against a variety of ROS [22], [23]. Use of these enzymes as therapeutic agents have had limited success [24], [25]. A number of problems hinder the use of antioxidant proteins as therapeutics, including difficult entry into cells due to their large size, expense, short half-life in the circulation, and antigenicity. Low-molecular-weight SOD mimetics with a redox-active metal center that catalyzes the dismutation reaction of superoxide can overcome some of these limitations. Selected metalloporphyrins possess multiple antioxidant properties. These properties include scavenging superoxide, hydrogen peroxide, peroxynitrite, and lipid peroxyl radicals [26], [27], [28], [29]. Metalloporphyrins have been shown to attenuate neutrophil influx and nitrotyrosine formation in a rat model of lung pleurisy [30]. Patel and Day [31] have suggested a number of inflammatory conditions in humans that are prime candidates for antioxidant therapy using metalloporphyrins. These conditions include acute respiratory distress syndrome, inflammatory bowel disease, myocardial infarction, and COPD. In the present study, we investigated whether manganese(III)meso-tetrakis(N,N′-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL 10150) provides a protective effect against tobacco smoke-induced inflammation and damage to the airways of rats.
Section snippets
Animals
Eleven week old male spontaneously hypertensive rats, free of respiratory disease, were purchased from Charles River (Raleigh, NC, USA) and quarantined for 1 week before exposure to tobacco smoke. This strain of rat was selected based on preliminary studies that demonstrated these rats to be highly sensitive to the effects of tobacco smoke exposure, with a robust inflammatory response. Animals were handled in accordance with standards established by the U.S. Animal Welfare Acts set forth in
Tobacco smoke exposure characteristics
TSP, nicotine, and carbon monoxide levels in the tobacco smoke during 2 d and 8 week studies are shown in Table 1.
BAL
Total number of cells in the BALF was increased significantly after either 2 d or 8 weeks of tobacco smoke exposure. Instillation of AEOL 10150 before exposure significantly decreased the number of BALF cells for both time points (Fig. 1). The number of BALF macrophages was increased significantly after either 2 d or 8 weeks of tobacco smoke exposure (Fig. 2). Instillation of
Discussion
Reactive oxygen species (ROS) have been shown to play an important role in numerous forms of inflammation [34], [35], [36], [37]. The gas and tar phases of tobacco smoke contain oxidants and free radicals [12] that may cause the sequestration of neutrophils from the pulmonary microcirculation as well as an accumulation of macrophages in respiratory bronchioles [38]. In addition, alveolar macrophages and neutrophils have the potential to produce large amounts of reactive oxygen intermediates
Acknowledgements
This work was supported in part by the National Institutes of Health PO1 HL31992, ES05707, RR00169 and a grant from the California Tobacco-Related Disease Research Program. The catalytic antioxidant (AEOL 10150) was provided by Incara Pharmaceuticals, Inc. The authors wish to thank Mr. Lalit Patel for his assistance with morphometric measurements in these studies.
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2021, Current Opinion in PharmacologyCitation Excerpt :Based on manganese complexes, numerous SOD mimetics such as AEOL10113 and AEOL10150 have been synthesized, which offer antioxidant effects inside the body. Studies have shown that AEOL10113 inhibits airway inflammation as well as bronchial hyperreactivity and AEOL10150 inhibits inflammation of the lungs that is induced by cigarette smoke [68–70]. Phosphodiesterase 4 (PDE4) inhibitors such as roflumilast and cilomilast are mainly used to treat pulmonary diseases such as COPD, asthma, and chronic bronchitis.
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2020, Redox BiologyCitation Excerpt :SOD mimetics include metalloporphyrins, such as AEOL 10113 and AEOL 10150 and manganese-containing molecules, such as M40419. These drugs have been shown to be effective in various in vivo animal models of oxidative stress, including tobacco smoke-exposed mice who show a reduced inflammatory response [70]. AEOL 10150 is used for the treatment of radiation pneumonitis and derivatives are currently being developed for COPD patients.
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1The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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2Dr. Crapo has an equity position in and is a consultant for Incara Pharmaceuticals, Inc.
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3Dr. Chang is a consultant for Incara Pharmaceuticals, Inc.