Current views in chronic obstructive pulmonary disease pathogenesis and management

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive lung dysfunction caused mainly by inhaling toxic particles and cigarette smoking (CS). The continuous exposure to ruinous molecules can lead to abnormal inflammatory responses, permanent damages to the respiratory system, and irreversible pathological changes. Other factors, such as genetics and aging, influence the development of COPD. In the last decade, accumulating evidence suggested that mitochondrial alteration, including mitochondrial DNA damage, increased mitochondrial reactive oxygen species (ROS), abnormal autophagy, and apoptosis, have been implicated in the pathogenesis of COPD. The alteration can also extend to epigenetics, namely DNA methylation, histone modification, and non-coding RNA. This review will discuss the recent progressions in COPD pathology, pathophysiology, and molecular pathways. More focus will be shed on mitochondrial and epigenetic variations related to COPD development and the role of nanomedicine as a potential tool for the prevention and treatment of this disease.

Keywords: Chronic obstructive pulmonary disease (COPD); Epigenetic alterations; Mitochondrial alterations; Mitochondrial epigenetics; Nanomedicine.

Fig. 1

Diagram illustrating the alveolus in lung tissue and the pathogenesis of COPD. Risk factors and drivers of COPD pathogenesis, showed in the top left of the figure, including cigarette smoking, which is the most common cause of COPD; inflammation, gene mutations, DNA damage, mitochondrial dysfunction, and exposure to drugs and toxins, resulting in an airway remodeling that induces emphysema and chronic bronchitis associated with COPD. The right image illustrates a cross-section of a distal airway and alveolar region, in which the surface of the lung contains different cell types, i.e., bronchial epithelium, epithelial basement membrane, and surfactant layers. Each alveolar tissue contains pneumocyte type I, pneumocyte type II, dysfunctional immune cells (macrophage cells), red blood cells, and capillary. ALF; alveolar lining fluid. Created with Biorender.com.

Fig. 2

Cigarette smoke-induced changes in mitochondrial function in COPD. Exposure to cigarette smoke and inflammation induce airway epithelium remodeling in chronic obstructive pulmonary disease. Impaired mitochondrial function, including fragmentation, mitochondrial ROS generation, mitochondrial membrane potential, mitophagy, lead to a metabolic switch from oxidative phosphorylation towards glycolysis. These changes are associated with increased expression of HIF-1α, mitochondrial fusion regulators, MNF2, MFN1, and OPA-1, fission modulators, DRP1, MFF, and FIS1, mitophagy markers LC3B, and Parkin, likely be linked to apoptosis-resistance, excessive proliferation, mitochondrial depolarization, and increased inflammation in airway epithelium in COPD. Red arrows indicate changes seen in COPD. Abbreviations: COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; HIF-1α, hypoxia-inducible factor; MnSOD, manganese superoxide dismutase; mtROS, mitochondria-derived reactive oxygen species; NFκB, nuclear factor; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; CLIC, chloride intracellular channel protein; LC3B, microtubule-associated protein 1-B light chain-3B; MFN1 &MFN2, mitofusin 1 &2; OPA1, optic. Created with BioRender.com.

Fig. 3

Schematic diagram illustrating COPD treatment. There is currently no cure for COPD, and the existing therapies focus on helping patients cope with the symptoms. The conventional therapies include different classes of therapeutic agents such as bronchodilators, corticosteroids and antibiotics, which are administrated either alone or in combination. Nanoparticles-based delivery systems classify into two main groups; organic and inorganic delivery systems. Viral-based gene delivery system, such as adeno-associated vectors (AAVs), and cellular therapy, such as mesenchymal stromal cells (MSCs), hold potential clinical applications in COPD treatment. Abbreviation: NPs; nanoparticles, PEG; polyethylene glycol, TiO₂; Titanium dioxide, CeO₂; cerium oxide, siRNA; small interfering RNA. Created with BioRender.com.