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Review
. 2023 Jan 6;12(1):142.
doi: 10.3390/antiox12010142.

Airway Smooth Muscle Regulated by Oxidative Stress in COPD

Hiroaki Kume  1 , Ryuki Yamada  1 , Yuki Sato  1 , Ryuichi Togawa  1
Affiliations
Review

Airway Smooth Muscle Regulated by Oxidative Stress in COPD

Hiroaki Kume et al. Antioxidants (Basel). .

Abstract

Since COPD is a heterogeneous disease, a specific anti-inflammatory therapy for this disease has not been established yet. Oxidative stress is recognized as a major predisposing factor to COPD related inflammatory responses, resulting in pathological features of small airway fibrosis and emphysema. However, little is known about effects of oxidative stress on airway smooth muscle. Cigarette smoke increases intracellular Ca2+ concentration and enhances response to muscarinic agonists in human airway smooth muscle. Cigarette smoke also enhances proliferation of these cells with altered mitochondrial protein. Hydrogen peroxide and 8-isoprostans are increased in the exhaled breath condensate in COPD. These endogenous oxidants cause contraction of tracheal smooth muscle with Ca2+ dynamics through Ca2+ channels and with Ca2+ sensitization through Rho-kinase. TNF-α and growth factors potentiate proliferation of these cells by synthesis of ROS. Oxidative stress can alter the function of airway smooth muscle through Ca2+ signaling. These phenotype changes are associated with manifestations (dyspnea, wheezing) and pathophysiology (airflow limitation, airway remodeling, airway hyperresponsiveness). Therefore, airway smooth muscle is a therapeutic target against COPD; oxidative stress should be included in treatable traits for COPD to advance precision medicine. Research into Ca2+ signaling related to ROS may contribute to the development of a novel agent for COPD.

Keywords: Ca2+ dynamics; Ca2+ sensitization; antioxidants; oxidants; phenotype changes; reactive oxygen species; tracheal smooth muscle.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Oxidants and antioxidants involved in COPD, and relationships between oxidative stress and the pathology related to this disease. Oxidative stress in the lungs results from increased exogenous and endogenous oxidants, and from reduced antioxidants. Endogenous oxidants are generated by mitochondrial respiration. Elevated production of endogenous oxidants continues after stopping smoking. Increased oxidative stress is caused by a lack of balance between oxidants and antioxidants. Exogenous oxidants are derived from cigarette smoke, air pollution and biomass smoke, etc.; endogenous oxidants are derived from inflammatory cells (macrophages, neutrophils) and airway epithelial cells. Oxidative stress results in emphysema in alveolar areas with decreased antiproteases, and in fibrosis in the small airways with increased transforming growth factor (TGF)-β. PM: small particulate matter, 8-OHdG: 8-hydroxy-2′-deoxyguanosine, 8-OHG: 8-oxo-7,8-dihydroguanosine, NOX: membrane-bound NADPH oxidases, Nrf2: nuclear erythroid-2 related factor 2, FOXO3a: forkhead box O3a. Arrows: activation, dotted arrows: inactivation.
Figure 2
Figure 2
Roles of senescence in inflammatory and airway epithelial cells to enhance oxidative stress in COPD. These senescent cells in the lungs synthesize inflammatory cytokines, growth factors proteases, and ROS more than intact cells in them, referred to as senescence-associated secretary phenotype (SASP). These phenotype changes in these cells perhaps potentiate not only the lung inflammation but also oxidative stress in COPD. ROS: Reactive oxygen species.
Figure 3
Figure 3
Interactions between inflammatory cells and airway smooth muscle cells in the pathophysiology of COPD. Functions (tension generation and response to contractile agents) of airway smooth muscle cells are altered (phenotype changes) by inflammatory substances (cytokines, growth factors, serine proteinases, phospholipids), which are synthesized in inflammatory cells (mast cells, eosinophils, etc.). Ca2+ signaling (Ca2+ dynamics and Ca2+ sensitization) is involved in the dysfunction of airway smooth muscle cells, leading to airflow limitation, β2-adrenergic desensitization and airway hyperresponsiveness (the pathophysiology features of asthma and COPD). Lyso-PC: lysophosphatidylcholine, TGF-β1: transforming growth factors-β1, PDGF: platelet-derived growth factor, ATP: adenosine triphosphate, S1P: sphingosine 1-phosphate, KCa: Ca2+-activated K+ channel, VDC: L-type voltage-dependent Ca2+ channel. Arrows: activation.
Figure 4
Figure 4
Involvement of oxidative stress in the dysfunctions of airway smooth muscle cells in COPD. Cigarette smoke enhances contractility caused by Ca2+ dynamics through TRP and SOCE. TNF-α and grows factors (TGF-β1, PDGF, and EGF) synthesize ROS, resulting in amplified cell proliferation through mitochondrial morphological changes, resulting in potentiated response to contractile agents (airway hyperresponsiveness) and increased mass of airway smooth muscle (airway remodeling, airflow limitation), which are pathological and pathophysiological characteristics of COPD. Nrf2 inhibits effects of TGF-β1 on oxidative stress. TRP: transient receptor potential, SOCE: store-operated Ca2+ entry. TNF-α: tumor necrosis factor-α, TGF-β1: transforming growth factor-β1, PDGF: platelet-derived growth factor, EGF: epidermal growth factor, Nrf2: nuclear erythroid-2 related factor 2, ROS: reactive oxygen species. Drp1: dynamin-related protein 1, Mfn2: mitofusin 2. Arrows: activation; dotted arrows: inactivation.
Figure 5
Figure 5
Roles of Ca2+ signaling in effects of oxidative stress related to COPD on airway smooth muscle. H2O2 and 8-iso-PGF2α, which are endogenous oxidants (oxidative stress biomarkers) synthesized in inflammatory cells, cause contraction with Ca2+ dynamics through Ca2+ channels and Ca2+ sensitization through the RhoA/Rho-kinase pathway. ATP, which is released from injury to airway epithelium caused by ROS, generates tension with Ca2+ dynamics through Ca2+ channels, and enhances muscarinic contraction with Ca2+ sensitization through the RhoA/Rho-kinase pathway. The Ca2+ signaling (Ca2+ dynamics and Ca2+ sensitization) may contribute to airflow limitation and airway hyperresponsiveness (pathophysiological features of COPD) caused by oxidative stress. ROS: reactive oxygen species, ATP: adenosine triphosphate, TP: thromboxane A2 receptors, P2X: P2X receptors (ATP-activated purinergic receptors), H2O2: hydrogen peroxide, 8-iso-PGF2α: 8-isoprostaglandin F2α.
Figure 6
Figure 6
Chemical compounds that potentially act as antioxidants, and mechanisms (Ca2+ signaling) related to oxidative stress in COPD. The chemical compounds, which are mimetics of SOD, include: superoxide dismutase, GPx: glutathione peroxidase, activator of Nfr2: nuclear erythroid-2 related factor 2, inhibitors of NOX: NADPH oxidases, MOP: myeloperoxidase, iNOS: inducible nitric oxide synthase and mitochondria-related (mt)-related antioxidants; they are effective on oxidative stress related to COPD in animal models and vitro studies. Biomarkers of oxidative stress related to COPD (H2O2, 8-iso-PGF2α) and external ATP which are released from injured airway epithelium cause contraction of airway smooth muscle via Ca2+ dynamics due to SOCE and Ca2+ sensitization due to Rho-kinase. These Ca2+ signaling pathways are also associated with proliferation of airway smooth muscle cell, and are inhibited by SKF96365 and Y-27632, respectively. ROS: reactive oxygen species, TRP: transient receptor potential, SOCE: store-operated Ca2+ entry, STIM 1: stromal interaction molecule 1, CaM: calmodulin, MLCK: myosin light chain kinase: MP: myosin phosphatase, MLC: myosin light chain, IP3: inositol trisphosphate, IP3R: IP3 receptor, GPCR: G protein-coupled receptor. Arrows: activation; dotted arrows: inactivation.
Figure 7
Figure 7
Precision medicine (personalized medicine) in COPD. The present guideline for COPD recommends that pharmacologic therapy for stable periods is carried out as a strategy based on symptoms (dyspnea) and frequency of exacerbations as treatable traits. Since COPD has heterogeneity, distinct phenotype classification is needed based on multidimensional approaches to advance from stratified medicine to personalized medicine in the management of COPD in near future. Although the clinical relevance of oxidative stress is still unclear, several oxidants can serve as treatable traits for development of precision medicine in COPD. See Section 6 in this text.
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