Aberrant neutrophil functions in stable chronic obstructive pulmonary disease: The neutrophil as an immunotherapeutic target

• COPD is a common, progressive chronic lung disease with few effective treatments.
• Neutrophils are central, with evidence of altered functions enhancing inflammation.
• Targeting neutrophils may normalise their behaviour, and improve disease control.

Chronic obstructive pulmonary disease (COPD) is a common, progressive and debilitating chronic inflammatory condition affecting the lungs, with significant systemic manifestations and co-morbidities. Smoking cigarettes is the main risk factor, but only a fifth of smokers have clinically significant airflow obstruction and the inflammation persists after smoking cessation. This suggests that smoking (and exposure to other inhaled toxins) may be necessary but not sufficient to cause COPD. Neutrophils are believed central to COPD and their accumulation and degranulation are associated with tissue damage, increased inflammation and disordered tissue repair. It was assumed that neutrophil activity and function were appropriate in COPD, responding to the presence of high levels of inflammation in the lung. However more recent studies of neutrophil function (including migration, reactive oxygen species generation, degranulation, phagocytosis and extracellular trap (NET) production) suggest that there is a general impairment in COPD neutrophil responses that predispose towards increased inflammation and reduced bacterial clearance. This may be amenable to correction and manipulating neutrophil intracellular pathways (such as phosphoinositide-3-kinase signalling) appears to restore some key COPD neutrophil responses. Targeting neutrophil intra-cellular signalling may provide a means to normalise neutrophil behaviour in COPD. This could lead to improvements in disease outcomes by reducing extraneous inflammatory burden. However further studies are needed to determine if these findings are relevant in vivo and whether this would impact positively upon health and disease.