Airway Smooth Muscle Regulated by Oxidative Stress in COPD

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.

Involvement of Lysophospholipids in Pulmonary Vascular Functions and Diseases

“…Therefore, the ATX-LPA pathway may be a novel therapeutic target for asthma. The ATX-LPA pathway enhances superoxide levels [37], suggesting that LPA may be involved in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD), which are partly related to oxidative stress [47].…”

“…Since LPC is the main component of oxidized low-density lipoprotein (oxLDL), which accumulates in atherosclerotic plaques, the effects of LPC on endothelial cells and vascular smooth muscle cells in the arteries play an essential role in the progression of atherosclerosis [57,58]. LPC also increases the generation of reactive oxygen species (ROS), and it enhances oxidative stress [59], inducing not only atherosclerosis but also various inflammatory diseases, such as asthma and COPD [47]. Furthermore, LPC causes intracellular calcium dynamics by increasing external Ca 2+ influx and Ca 2+ release from the endoplasmic reticulum [60].…”

Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies

“…It has been shown that ROS convert inactive latent TGF-β to active formation by oxidizing latency association protein (LAP) ( Pociask et al, 2004 ). Through activating TGF-β pathway, H 2 O 2 drives epithelial mesenchymal transition (EMT) in lung epithelial cells to promote lung fibrosis ( Kume et al, 2023 ).…”

TRPV4 Activation during Guinea Pig Airway Smooth Muscle Contraction Promotes Ca2+ and Na+ Influx

“…Moreover, it also assists with defensive reflexes, such as coughing [ 5 , 7 ]. Numerous lung disorders, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), and asthma, have been associated with the dysfunction of the ASM [ 2 , 8 , 9 , 10 , 11 , 12 ]. Alterations in the number and size of ASM cells and their contractile activity (i.e., excessive constriction and reduced relaxation) can lead to airway remodeling, hyperreactivity, and inflammation [ 9 , 10 , 11 , 13 ].…”

“…Numerous lung disorders, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), and asthma, have been associated with the dysfunction of the ASM [ 2 , 8 , 9 , 10 , 11 , 12 ]. Alterations in the number and size of ASM cells and their contractile activity (i.e., excessive constriction and reduced relaxation) can lead to airway remodeling, hyperreactivity, and inflammation [ 9 , 10 , 11 , 13 ]. Several mechanisms are responsible for these changes, including signaling pathways mediated by G protein-coupled receptor (GPCR) and nonselective cationic channels (NSCCs) such as store-operated Ca 2+ (SOC) channels, transient receptor potential (TRP) channels, and stretch-activated channels [ 5 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”