Novel aspects of pathogenesis and regeneration mechanisms in COPD

Abstract

Chronic obstructive pulmonary disease (COPD), a major cause of death and morbidity worldwide, is characterized by expiratory airflow limitation that is not fully reversible, deregulated chronic inflammation, and emphysematous destruction of the lungs. Despite the fact that COPD is a steadily growing global healthcare problem, the conventional therapies remain palliative, and regenerative approaches for disease management are not available yet. We aim to provide an overview of key reviews, experimental, and clinical studies addressing lung emphysema development and repair mechanisms published in the past decade. Novel aspects discussed herein include integral revision of the literature focused on lung microflora changes in COPD, autoimmune component of the disease, and environmental risk factors other than cigarette smoke. The time span of studies on COPD, including emphysema, chronic bronchitis, and asthmatic bronchitis, covers almost 200 years, and several crucial mechanisms of COPD pathogenesis are described and studied. However, we still lack the holistic understanding of COPD development and the exact picture of the time-course and interplay of the events during stable, exacerbated, corticosteroid-treated COPD states, and transitions in-between. Several generally recognized mechanisms will be discussed shortly herein, ie, unregulated inflammation, proteolysis/antiproteolysis imbalance, and destroyed repair mechanisms, while novel topics such as deviated microbiota, air pollutants-related damage, and autoimmune process within the lung tissue will be discussed more extensively. Considerable influx of new data from the clinic, in vivo and in vitro studies stimulate to search for novel concise explanation and holistic understanding of COPD nowadays.

Keywords: autoimmune COPD; chronic obstructive pulmonary disease; dysbiosis in COPD; occupational COPD.

Figures

Figure 1

Mechanisms underlying COPD development. Notes: (A) The airway epithelium consisting of several diverse cell types maintains a balanced interaction with normal lung microbiota, and only regulatory signals are induced. Progenitors (mesenchymal stem cells) are recruited from circulation when needed. (B) Pathogenic bacteria (eg, Streptococcus pneumoniae, Pseudomonas aeruginosa) activate proinflammatory signaling pathways in the epithelium and also release chemokines and cytokines themselves. In parallel to air pollutants, cigarette smoke, oxidants also induce similar changes (fine red arrows). Air pollutants, including cigarette smoke, are a rich source of oxidants capable to recruit macrophages and neutrophils. Pollution also decreases a pool of progenitor cells in the circulation and locally (fine red arrow). Inflammatory cells (eg, neutrophils, dendritic cells, monocytes/macrophages, cytotoxic T-cells) arrive at the sites of inflammation and become the additional source of cytokines, oxidants, and proteases. CD4 and CD8 T-cells (Tc1/Th1-dominant) are present and release chemokines and perforins. At the same time, representatives of normal microbiota induce relatively weak signals to prevent the exaggeration of the inflammation. These stimuli-induced processes result in alveolar wall cells and vascular endothelial cells apoptosis/loss, and extracellular matrix proteolysis. Inflammation might be further triggered by elastin fragments. Structural alveolar disintegration, loss of epithelium and endothelium, and the overall inflammatory ambience are seen. Abbreviations: AEI and AEII, alveolar type I and II epithelial cells; AM, alveolar macrophages; EC, endothelial cells.