Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by a decreased airflow due to airway narrowing that, once it occurs, is not fully reversible. The disease usually is progressive and associated with an enhanced inflammatory response in the lungs after exposure to noxious particles or gases. After removal of the noxious particles, the inflammation can continue in a self-sustaining manner. It has been established that improper activation of neutrophils lies at the core of the pathology. This paper provides an overview of the mechanisms by which neutrophils can induce the pulmonary damage of COPD. As the pathogenesis of COPD is slowly being unraveled, new points of intervention are discovered, some of which with promising results.

Keywords::

• chronic obstructive pulmonary disease control
• infectious agents
• infiltration
• inflammation
• neutrophil
• oxidative stress
• protease imbalance
• treatment

Financial & competing interests disclosure

No external funding for this study was used. The University College Roosevelt covered all costs associated with the development and the publishing of the present manuscript. The corresponding author had full access to the data and final responsibility for the submission of the publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Chronic obstructive pulmonary disease (COPD) is a complex disease in which neutrophils play a central role. However, there are many different interactions with endothelial and pulmonary cells as well as with other leukocytes.

• • In COPD, regulation of neutrophil activation is disturbed. Not only are the neutrophils overstimulated, their pathways of activation and inhibition are altered at the molecular level.

• • The main alterations in neutrophils are: increased infiltration, increased longevity, increased activation and increased necrosis. All of this leads to increased levels of neutrophilic products in the lungs, which in turn lead to pulmonary damage.

• • An imbalance of neutrophil elastase and its inhibitor, α₁-antitrypsin, and of matrix metalloprotease-9 and its inhibitor, tissue inhibitor of matrix metalloproteases 1 (TIMP-1), lead to severe pulmonary remodeling. However, many other pro- and anti-inflammatory mediators are also altered in COPD which further contributes to these imbalances.

• • The recent body of research into COPD has provided many new options of intervention. Unfortunately, the altered responsiveness of neutrophils has been a major obstacle for successful implementation.

• • Although there is no cure for COPD and new drugs still need to be developed, current treatment options such as statins may still benefit more patients if caregivers become more aware of their benefits in COPD. Corticosteroid treatment may be detrimental to the effectiveness of statins.

• • Reinstating normal neutrophil reactivity seems a promising target in the treatment of COPD. Ectoine does this by reinstating normal apoptosis and shows promising results.

• • Another line of research tries implementing anti-inflammatory drugs designed for rheumatoid arthritis in COPD. Often, these drugs were effective but had too many side effects when administered systemically, but local administration via inhalation in COPD may overcome this drawback.

Notes