Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation

Abstract

Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction. COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma. Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression. Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology. Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease–antiprotease imbalance, and oxidative stress. Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients. For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status.

Neutrophil Elastase Differentially Regulates Interleukin 8 (IL-8) and Vascular Endothelial Growth Factor (VEGF) Production by Cigarette Smoke Extract

“…CS is itself a rich source of oxidants, and it triggers production of oxidants from inflammatory cells (6). CS directly or indirectly through oxidants induces chronic inflammation by releasing inflammatory cytokines such as TNF-␣ (20) and IL-8 (21).…”

“…However, the mechanism of CS and COPD development is not fully understood and could be explained by different hypotheses including inflammation, protease-antiprotease imbalance, oxidant stress (3)(4)(5)(6), apoptosis (7), and accelerated lung aging (8). Among them, inflammation, oxidative stress, and protease-antiprotease imbalance have been suggested as a pathogenic triad in COPD (6). Lung inflammation caused by CS is generally associated with an influx of inflammatory cells such as neutrophils, macrophages, and CD8 ϩ T lymphocytes (9).…”

“…CS itself contains a high concentration of reactive oxygen species, which causes tissue destruction and DNA damage (10). Moreover, CS triggers generation of additional reactive oxygen species, and reactive oxygen species amplify inflammation, suggesting cross-talk between oxidative stress and inflammation (6,11). The protease-antiprotease imbalance arises from the activity of inflammatory cells, especially neutrophils recruited by CS.…”

COPD affected lung tissue remodelling due to the local distribution of MMP-2, TIMP-2, TGF-β1 and HSP-70

“…In COPD, mostly the pathogenic triad of chronic infl ammation, altered and disrupted remodelling, as well as oxidative stress correspond to the cytopathology and histopathology [6]. Altered infl ammatory response, cell and tissue damage, also abnormal repair of cell and tissue injury confi rms defective remodelling of the extracellular matrix (ECM) in lung airways.…”

“…Increased levels of TIMPs promote ECM accumu lation towards fi brosis, whereas the decrease of TIMPs enhances proteolysis in ECM. TIMPs regulate MMPs within ECM by inhibiting their maintenance [1,6,7]. Overall eff ective ECM remodelling in lung tissue is regulated as a dynamic balance between the proper cell and tissue renewal and, conversely, the tissue degradation.…”