Progress in the mechanism and targeted drug therapy for COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is emphysema and/or chronic bronchitis characterised by long-term breathing problems and poor airflow. The prevalence of COPD has increased over the last decade and the drugs most commonly used to treat it, such as glucocorticoids and bronchodilators, have significant therapeutic effects; however, they also cause side effects, including infection and immunosuppression. Here we reviewed the pathogenesis and progression of COPD and elaborated on the effects and mechanisms of newly developed molecular targeted COPD therapeutic drugs. Among these new drugs, we focussed on thioredoxin (Trx). Trx effectively prevents the progression of COPD by regulating redox status and protease/anti-protease balance, blocking the NF-κB and MAPK signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the cAMP-PKA and PI3K/Akt signalling pathways. The mechanism by which Trx affects COPD is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses. In addition, Trx also improves the insensitivity of COPD to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (MIF). Taken together, these findings suggest that Trx may be the ideal drug for treating COPD.

Fig. 1

The pathogenesis of COPD is complex and diversified. Oxidative stress may participate in various the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases and enhancing lung inflammation through activation of redox-sensitive transcription factors. Under the stimulation of cigarette smoke, pathogen infection and other factors, oxidative stress is induced and the pulmonary inflammatory cells (neutrophils, CD8 T lymphocytes, macrophages) accumulate, resulting in a large number of reactive ROS. The inflammatory cells are activated by the NF-κB, p38MAPK and PI3K signalling. Inflammatory cells (mainly neutrophils) migrate from the circulation to the inflammatory site under sequential regulation involving cytokines and adhesion molecules such as selectin. Proteases are involved in tissue remodelling, inflammation and ECM degradation, thereby participating in the pathological process of COPD. Inflammatory cytokines and chemokines, such as LTB4, IL-8 and TNF-α, and other mediators are secreted into the lungs to aggravate the lung tissue damage and promote inflammatory responses. PDE4 decreases cAMP levels in inflammatory cells and promotes inflammatory cell activity and the release of inflammatory factors. Chronic inflammation stimulates the increase of EGFR and TGF-β1. Activated EGFR is involved in the proliferation of the airway epithelial goblet cells and mucus production. TGF-β1 chemoattracts neutrophils, macrophages and mast cells, and activates PI3K/Akt and/or p38MAPK signalling to induce pulmonary fibrosis and EMT. Endothelin-1 (ET-1) produced by endothelial cells, stimulates the contraction and proliferation of vascular smooth muscle cells and the liver to produce more CRP, and it also induces the synthesis of VEGF. B-type natriuretic peptide (BNP) antagonises renin angiotensin aldosterone system, dilates blood vessels and reduces peripheral vascular resistance, and C-type natriuretic peptide (CNP) dilates blood vessels and inhibits the proliferation of vascular smooth muscle cells

Fig. 2

New molecular targeted drugs. Based on the molecular mechanism of COPD, many new molecular targeted drugs have been developing in recent years. Antioxidants scavenge ROS and inhibit oxidative stress in the lungs and reduce cellular damage and inflammation. Protease inhibitors restore the balance between protease and anti-protease by inhibiting. proteases. Cytokine and chemokine inhibitors play an important role in reducing the inflammatory response. Adhesion molecule inhibitors can block inflammatory cells, which continuously migrate from the blood vessels to the tissue. PDE4 inhibitors inhibit PDE4 production to increase the cAMP activity in cells. In the occurrence and development of COPD, the signalling molecules, such as NF-κB, MAPK, PI3K and VIP help regulate inflammation and airway remodellings, and represent plausible targets for the development of therapeutic candidates. Candidate drugs include inhibitors of p38MAPK, NF-κB and PI3K, and vasoactive intestinal peptide (VIP). The inhibitor of EGFR reduces internalisation of EGFR but does not reduce mucin stores. TGF-β inhibitor reduces a fibrotic airway remodelling and downregulates MMP expression, Endothelin inhibitors prevent the progression of pulmonary hypertension in COPD. Adenosine A_2a receptor inhibits neutrophil superoxide production, phagocytosis, adhesion and cytokine release. Macrolides reduces the inflammation of COPD by regulating the PI3K/Akt-Nrf2 pathway and control transcription factors such as NF-κB and AP-1 to inhibit the production of inflammatory cytokines. PPAR agonists exert antioxidant and anti-inflammatory effects by down-regulating NF-κB and other pro-inflammatory transcription factors

Fig. 3

Trx improves GC through MIF. One GC resistance mechanism impaired by the MIF is the loss of GC sensitivity via inhibition of MKP-1. MKP-1 is induced by GC to mediate GC inhibition of ERK, JNK and p38MAPK activities and cytokine production. MIF inhibits GILZ expression via a unique set of effects on transcription factor expression and phosphorylation. MKP-1 and MAPK activation are regulated by MIF via GILZ. Both intracellular and extracellular Trx bind to MIF and form a heterodimer to prevent the MIF entry into cells and MIF-induced glucocorticoid resistance

Fig. 4

Trx prevents and relieves COPD pathogenesis through multiple molecular mechanisms. Trx eliminates MIF to improve glucocorticoid resistance and eliminates ROS and inhibits neutrophil infiltration by regulating adhesion molecules to suppress the production of cytokines to reduce oxidative stress and inflammation. Trx exerts its anti-oxidative and anti-inflammatory effects by regulating the NF-κB, MAPK, PI3K/Akt and cAMP-PKA pathways. Trx also inhibits the airway neutrophil recruitment by down-regulating the expression of neutrophil L-selectin on circulating neutrophils. Trx is subtle in regulating the balance between protease and antiprotease. Trx has inhibitory effect on both, but it is asymmetric in its inhibition. Trx has stronger inhibitory effects on over-generated proteases, thus maintaining the balance of the protease–antiprotease system. Moreover, Trx down-regulates the expression of EGFR and TGF in the airway to reduce mucus secretion, airway remodelling and pulmonary fibrosis