Role of thioredoxin in chronic obstructive pulmonary disease (COPD): a promising future target

Abstract

Introduction: Thioredoxin (Trx) is a secretory protein that acts as an antioxidant, redox regulator, anti-allergic, and anti-inflammatory molecule. It has been used to treat dermatitis and inflammation of the digestive tract. In the lungs, Trx has a significant anti-inflammatory impact. On the other hand, Chronic Obstructive Pulmonary Disease (COPD) is one of the significant causes of death in the developed world, with a tremendous individual and socioeconomic impact. Despite new initiatives and endless treatment trials, COPD incidence and death will likely escalate in the coming decades.

Areas covered: COPD is a chronic inflammatory disease impacting the airways, lung parenchyma, and pulmonary vasculature. Oxidative stress and protease-antiprotease imbalances are thought to be involved in the process. The most popular respiratory inflammatory and allergic disorders therapies are corticosteroids and β-receptor agonists. These medications are helpful but have some drawbacks, such as infection and immunosuppression; thus, addressing Trx signalling treatments may be a viable COPD treatment approach. This review shall cover the pathophysiology of COPD, the pharmacognosy of anti-COPD drugs, including the assets and liabilities of each, and the role and mechanism of Trx in COPD treatment.

Expert opinion: Limited research has targeted the thioredoxin system as an anti-COPD drug. Spectating the increase in the mortality rates of COPD, this review article would be an interesting one to research.

Keywords: COPD; Inflammation; Oxidative stress; ROS; Thioredoxin.

Fig. 1

Pathophysiology of COPD. Chronic smoking (CS), which causes oxidative (OS) stress, proteolysis, and chronic inflammation, is linked to COPD development. CS causes a substantial amount of reactive (ROS) oxygen species, disrupting the harmony between free radicals and antioxidants, intensifying inflammatory responses, and accelerating lung cell damage

Fig. 2

Proposed pathway of thioredoxin inhibiting recruitment of inflammatory cells and proteases. Smoking and other irritants cause epithelial cells and macrophages to start releasing a number of chemotactic substances that draw inflammatory cells to the lungs. These substances include CCL2, which attracts monocytes by acting on CCR2, CXCL1, and CXCL8, which attract neutrophils. Along with macrophages and epithelial cells, these inflammatory cells release proteases like MMP-9 that break down elastin and lead to emphysema. Mucus hypersecretion is also brought on by neutrophil elastase. TGFβ- is also released by macrophages and epithelial cells, which promotes the growth of fibroblasts and causes fibrosis in the lower airways. Many studies have revealed a significant role of thioredoxin in regulating this pathway

Fig. 3

Thioredoxin reactivating PTEN. PTEN is an antagonist of PIP3. PTEN is deactivated under oxidative stress, which triggers the PDK1 pathway. Thioredoxin is also dimerized during oxidative stress or can form a dimer with PTEN. However, extracellular thioredoxin has the ability to restore the redox equilibrium of the cell, thereby activating PTEN once more and inhibiting the pi3-apk pathway

Fig. 4

Conserved Cysteine residues in the thioredoxin active site sequence

Fig. 5

Promotor region of human thioredoxin. Three Sp1 (specificity protein 1)-binding sites are present between − 244 bp and − 183 bp, along with the first transcription start site (TS1), which is positioned at − 110 bp. With a TATA box at − 102 bp, the TS2 is only at − 74 bp. antioxidant responsive element (ARE), oxidative stress responsive element (ORE)

Fig. 6

Crosstalk of thioredoxin with other antioxidants. Peroxidoxin can reduce the hydrogen peroxide after which it is reduced by Thioredoxin, while thioredoxin reductase (TrxR) reduces oxidized Trx in a NADPH-dependent manner. GPX combines the oxidation of GSH with the reduction of Hydrogen peroxide. Glutathione reductase (GR) reduces oxidized glutathione disulfide (GSSG) in the presence of NADPH

Fig. 7

Thioredoxin regulating NF-KB pathway. In a normal scenario NF-KB is in an inactive state, but when exposed to oxidative stress, it activates and enters the nucleus to start the transcription of inflammatory genes. However, thioredoxin has been observed to suppress the ubiquitination of I-KB, which in turn inhibits the insertion of NF-KB into the nucleus