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Recent Developments in the Role of Reactive Oxygen Species in Allergic Asthma

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43 Review Article Recent developments in the role of reactive oxygen species in allergic asthma Jingjing Qu1,2*, Yuanyuan Li1*, Wen Zhong1, Peisong Gao2, Chengping Hu1 1Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; 2Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, MD, USA Contributions: (I) Conception and design: J Qu, Y Li, P Gao, C Hu; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: W Zhong; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. *These authors contributed equally to this work. Correspondence to: Chengping Hu. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha 410008, China. Email: [email protected]; Peisong Gao, MD, PhD. The Johns Hopkins Asthma & Allergy Center, 5501 Hopkins Bayview Circle, Room 3B.71, Baltimore, MD 21224, USA. Email: [email protected]. Abstract: Allergic asthma has a global prevalence, morbidity, and mortality. Many environmental factors, such as pollutants and allergens, are highly relevant to allergic asthma. The most important pathological symptom of allergic asthma is airway inflammation. Accordingly, the unique role of reactive oxygen species (ROS) had been identified as a main reason for this respiratory inflammation. Many studies have shown that inhalation of different allergens can promote ROS generation. Recent studies have demonstrated that several pro-inflammatory mediators are responsible for the development of allergic asthma. Among these mediators, endogenous or exogenous ROS are responsible for the airway inflammation of allergic asthma. Furthermore, several inflammatory cells induce ROS and allergic asthma development. Airway inflammation, airway hyper-responsiveness, tissue injury, and remodeling can be induced by excessive ROS production in animal models. Based on investigations of allergic asthma and ROS formation mechanisms, we have identified several novel anti-inflammatory therapeutic treatments. This review describes the recent data linking ROS to the pathogenesis of allergic asthma. Keywords: Allergic asthma; reactive oxygen species (ROS); antioxidants Submitted Aug 30, 2016. Accepted for publication Dec 15, 2016. doi: 10.21037/jtd.2017.01.05 View this article at: http://dx.doi.org/10.21037/jtd.2017.01.05 Introduction obvious involvement of the adaptive immune system, such as type 2 helper T cells (Th2 cells) (1,2). Allergic asthma Asthma is a characteristic of different phenotypes of chronic is more prevalent than non-allergic asthma. In our review, airway inflammation, including allergic asthma and non- we focus on allergic asthma. In susceptible patients, the allergic (intrinsic) asthma. Allergic asthma is a chronic main clinical symptoms of allergic asthma are shortness of airway inflammatory disease in which many immune breath, chest tightness and wheezing (3). Allergic asthma is regulatory cells within the immune system work together very common and afflicts 8.5% of the U.S. population and with epithelial cells to cause smooth muscle contraction, is estimated to cause >3,000 deaths and to cost more than enhance airway hyper-reactivity (AHR), increase mucus $56 billion annually in lost work and medical expenses (4). secretion and stimulate bronchospasm. Non-allergic asthma Many patients use corticosteroids and a short- or long-acting often develops later in life and, per its definition, has neither β-adrenergic agonist to treat asthma; however, in 5–10% immunoglobulin E (IgE) reactivity to allergens nor any patients, therapy fails (5). © Journal of Thoracic Disease. All rights reserved. jtd.amegroups.com J Thorac Dis 2017;9(1):E32-E43 Journal of Thoracic Disease, Vol 9, No 1 January 2017 E33 It is well known that reactive oxygen species (ROS), regulatory proteins alter airway remolding and function endogenous nitric oxide (NO) and NO derived reactive in smoking-related airway disease, especially allergic nitrogen species (RNS) have been reported to mediate asthma (19). CSE can damage bronchial epithelial cells oxidative stress and airway inflammation and pathogenesis. from asthmatic patients through regulation of apoptosis- However, ROS are more common in allergic asthma inducing factors, which is implicated in DNA damage and development (6,7). Hence, in our review, we mainly focus ROS-mediated cell-death (18). Recently the nanoparticles on the relationship between ROS and allergic asthma. ROS, (NPs) that particle diameter less than 100 nano including such as hydrogen peroxide, may be directly or indirectly engineering NPs and natural formation of the NPs already involved in epithelial cell apoptosis and inactivation of exist in the air, such as photochemical smog, forest fires, antioxidant enzymes and contribute to allergic asthma car exhaust. The NPs could exacerbate the inflammatory (8-11). ROS are derived from endogenous or exogenous responses in lungs. PM and is consistently involve in oxidants. Endogenous ROS are composed of mitochondria, respiratory diseases, such as asthma, through oxidative stress NADPH, and the xanthine/xanthine oxidase (XO) system. pathways (20). PM is capable of generating free radicals, Exogenous sources of ROS production have been linked to the metals on their surface takes part in redox cycling or strong oxidizing gases, such as ozone (O3), sulfur dioxide depletion of anti-oxidant glutathione function and PM2.5 (SO2), nitrogen dioxide (NO2) and particulate matter (PM), means the particle diameter less than or equal to 2.5 μm which are a major component of air pollution (12,13). (21,22). Josephine was the first to estimate population- The oxygen stress level in asthma is increased because of level health effects through ROS activity measurements inflammatory cells in vivo, and cigarette smoke (CS) or PM and to use an epidemiologic approach to link PM2.5 ROS produces ROS in vitro. For example, compared with normal to asthma. The results showed that reducing water-soluble subjects, the level of H2O2 and superoxide that are produced PM2.5 (WS-PM2.5) dithiothreitol (DTT) activity may by eosinophils and neutrophils are significantly increased significantly decreasing the incidence of asthma (23). A in asthma patients (14). Increased levels of ROS can cause meta-analysis showed that particle components play a pro- harmful pathophysiological disorders of allergic asthma. oxidant role that thereby promote airway inflammation (24). Studies have reported that excessive ROS can damage It is well known that the aryl hydrocarbon receptor (AhR) DNA, carbohydrates, proteins, and lipids, ultimately is recognized as a receptor for environmental contaminants. leading to an increased inflammatory response in allergic AhR induction of increased mucin production is partially asthma (15,16). In this review, we will discuss the updated mediated by ROS generation, and antioxidant therapy can pathophysiological and mechanisms of oxidative stress mitigate AhR-induced mucus hyper-secretory diseases (25). relating to allergic asthma. AhR ligands have been shown to induce mast cells to increase ROS production in asthma (26). Ozone could be an inflammatory mediator by scavenging ROS; for example, Exogenous oxidants and allergic asthma electron-rich olefins could be used to treat asthma (27). Patients’ exposure to the environmental atmosphere is the Additionally, asbestos, coal, and pollens also induce main way that exogenous oxidative stress is induced (17). CS excessive ROS formation levels that are related to immune is a complex mixture including more than 4,000 different responses associated with allergic asthma (28,29). compounds. It has been demonstrated that inhaled CS can increase ROS levels. Most of these compounds have ability Endogenous oxidants and allergic asthma to generate ROS during their metabolism. The mechanism of CS induced inflammation is incorporated with oxidative Intracellular ROS are mainly composed of mitochondria, stress leading to cell death and oxidative DNA damage NADPH oxidase, and the xanthine/XO system. The via apoptosis and/or necrosis (7). It was reported that generation of superoxide anion is mediated by mitochondria antioxidants have the ability to protect cells from cigarette and NADPH oxidase. It was reported that eosinophils and smoke extract (CSE) induced apoptosis (18). Isolated human neutrophils could produce more superoxide anion from airway smooth muscle (hASM) cells were used to determine asthmatic patients compared with healthy subjects due to Ca2+ responses and hASM proliferation, as well as ROS level NADPH oxidase activation during asthma (30). The NADPH and cytokine generation, by incubating these cells in the oxidase, dual oxidase 1 (DUOX1), critically contributes presence or absence of CSE. The results revealed that Ca2+ to airway epithelial secretion of interleukin-33 (IL-33), © Journal of Thoracic Disease. All rights reserved. jtd.amegroups.com J Thorac Dis 2017;9(1):E32-E43 E34 Qu et al. ROS in asthma which is dependent on Src/EGFR pathway activation in during asthma (38). A study suggested that proteinase- asthma (31). Leukotriene C4 (LTC4) can elicit nuclear activated receptor 2 (PAR-2) is involved in airway translocation of NADPH oxidase 4 (NOX4), ROS inflammation regulation through oxidative stress, leading accumulation and oxidative DNA damage. LTC4 inhibitors, to increased DUOX-2/ROS pathway activation in airway
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