Neutrophils and Emerging Targets for Treatment in Chronic Obstructive Pulmonary Disease

Mariska Meijer; Ger T Rijkers; Frans J van Overveld


Expert Rev Clin Immunol. 2013;9(11):1055-1068. 

In This Article

Neutrophils in COPD

One of the diseases most clearly marked by neutrophil involvement is COPD. COPD is characterized by a decreased airflow due to airway narrowing that, once it occurs, is not fully reversible. It is usually progressive and associated with an abnormal inflammatory response in the lungs after exposure to noxious particles or gases. The pathological processes underlying airflow limitation in COPD consist of chronic bronchitis, small airway disease, also known as bronchiolitis, and lung emphysema, although not all patients express all disease entities.[61,62] Chronic bronchitis is clinically characterized by 'the presence of cough and sputum production for at least 3 months in each of two consecutive years', and it 'is an independent disease entity that may precede or follow the development of airflow limitation' according to the GOLD criteria.[63] Emphysema is a pathological process of alveolar destruction during which no apparent fibrosis takes place. Together with bronchiolitis these conditions lead to a reduction of gaseous exchange during respiration.

The main diagnostic marker for COPD is the volume of air exhaled during the first second of forced expiration (FEV1).[62] When assessing the severity of this disease, also the number and severity of exacerbations should be taken into account.[64] The reason is that patients with more exacerbations have a worse prognosis, a worse health status and an enhanced inflammatory profile with increased numbers of neutrophils.

A1AT deficiency is known as a risk factor, because A1AT inhibits NE and therewith limits lung damage.[44] In less than 2% of the COPD cases, the disease results from an A1AT deficiency,[65] but in most cases COPD develops as a result of an unhealthy environment, with high exposure to dust or environmental pollution.[62,66] The main environmental trigger for COPD is smoking, with smokers accounting over 80% of COPD patients. Although smoking therefore is the primary cause of COPD, only 15–25% of smokers develops this disease, indicating that only smokers susceptible to the disease will develop it.[62] Which factors determine COPD susceptibility is largely unknown and thus there is still much to learn about the etiology and pathophysiological pathways of COPD. A better understanding of COPD may enable the development of better medication and prevention. Currently, the main treatment consists of bronchodilators and corticosteroids. These components are effective in treating the symptoms, which by itself is of value, but not the underlying pathology. Bronchodilators and corticosteroids are also first choice treatments of asthma. It is however important to note that COPD and asthma are two quite different diseases (Table 1); though for a long time they have been confused. In asthma, mast cells, lymphocytes and eosinophils, play an important role, while neutrophils only are important in some relatively rare, and severe, subtypes of asthma.[67] In COPD, on the other hand, neutrophils seem to play a major role, as neutrophil activation in the lungs correlates directly with the severity of the symptoms.[67] Four main processes have been identified which influence the occurrence of COPD. First of all, in COPD patients there is excessive neutrophil infiltration in the lungs. Second, the accumulation of neutrophils leads to high levels of a number of inflammatory modulators, including proteases that have been associated with tissue damage and chemoattractants that recruit additional inflammatory cells.[68,69] Furthermore, components have been identified that increase the longevity of neutrophils in COPD, which substantially adds to the accumulation of these cells in the lungs. Finally, in comparison with those of healthy individuals, the neutrophils of COPD seem to respond differently to many chemical signals that normally regulate the immune response.[69–71] This has impeded the progress of research to the causes and especially to possible interventions for COPD.