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

Lung Infiltration

As mentioned before, COPD is characterized by an excessive neutrophil infiltration in the lungs. In healthy controls, the median neutrophil count in induced sputum is 53%.[72] In COPD patients, a median of 80% has been found, while for example eosinophil levels, an important hallmark of asthma, had not changed.[72] The high number is a consequence of an increase in neutrophil chemotaxis and longevity. It has been found that activated endothelial cells modulate apoptotic factors in neutrophils during neutrophil extravasation.[73] Endothelial secretion of granulocyte macrophage-colony stimulating factor (GM-CSF), and possibly other factors, play a role in this and its effect continues after extravasation is completed.[73] However, more recent studies suggest that GM-CSF does not regulate neutrophil apoptosis in COPD in the same way it regulates this process in healthy controls.[70] Therefore, it cannot be presumed CM-CSF acts via the same pathways in pulmonary neutrophils in COPD as it does in those of healthy individuals. This complicates the search for an effective intervention with this pathway as a treatment for COPD. The lifespan of pulmonary neutrophils in COPD is prolonged because apoptotic pathways are suppressed. Neutrophils in COPD patients express the anti-apoptotic bcl-xl and Mcl-1 gene more strongly than healthy controls, whereas the expression of the pro-apoptotic Bac gene is decreased in these patients.[74] Moreover, neutrophils of COPD patients have been found to associate with immunoglobulin free light chains (FLC), which, by mechanisms as yet unknown, are also capable of increasing neutrophil lifespan. Antagonizing FLC has led to a decreased pulmonary influx of neutrophils in murine studies.[75] All of these observations offer potential targets for treatment. Many of them are currently under research.

An important chemoattractant for neutrophils is IL-8 (CXCL8), which can be released by activated epithelial cells as well as immune cells such as macrophages and mast cells. In COPD patients, an increase of IL-8 in bronchoalveolar lavage (BAL) fluid has been found and IL-8 levels have been positively correlated with neutrophilic infiltration in the lung.[62,72] More detailed studies found that cigarette smoke (CS) also induces IL-8 expression by pulmonary cells, especially bronchiolar smooth muscle cells.[62,76] Furthermore, the chemotaxis of neutrophils in response to IL-8 is increased in COPD.[77] It is hypothesized to be due to priming of neutrophils by CS, possibly via TNF-α, which normally induces this response and whose levels are found to be increased in smokers.[77,78] Because of these findings, it has been suggested that TNF-α levels are the reason why the progression of COPD slows down if people quit smoking.[78] However, a later study using an TNF-α antagonist suggests the role of TNF-α is altered in COPD.[71]

Besides the recruitment of neutrophils, IL-8 also induces the activation of p38 mitogen-activated protein kinase (MAPK).[76] Since IL-8 can also be secreted by activated neutrophils, the observed deregulation of IL-8 could also account for the self-sustaining characteristics of COPD.[71] At this moment, both p38 MAPK and a precursor of IL-8, NF-κB, are targeted for treatment.

p38 MAPK

The p38 MAPK signaling pathway leads to an increased expression of proinflammatory cytokines by upregulating TNF-α transcription and stabilizing cytokine mRNA.[79] Activation of this pathway has been correlated to the degree of lung function impairment as well as the level of alveolar inflammation.[80] Systemic inhibition of p38 MAPK reduces neutrophil infiltration during pulmonary infections without affecting other leukocytes.[79] Moreover, p38 MAPK inhibition has been correlated with a decreased expression of IL-6 in COPD patients.[81] As murine studies have indicated IL-6 and TNF-α to be potent instigators of lung emphysema, the development of COPD treatment based on p38 MAPK inhibition seems attractive.[76] One drug aiming to do this was developed for rheumatoid arthritis. Though oral administration led to many adverse side effects, other studies indicate that these are far less pronounced when the drug is administered intrapulmonary. p38 MAPK inhibitors therefore seem a promising new line of treatment. Currently, several clinical trials explore the feasibility of this approach.[82]


NF-κB is a central signaling molecule capable of inducing the production of inflammatory mediators, such as IL-8 and TNF-α, as well as lymphocyte activation, among numerous other functions.[83] In COPD, NF-κB signaling can be deregulated and thus this proinflammatory pathway seemed an attractive target for pharmacological intervention.[69] Indeed, interfering with this signaling pathway decreased responsiveness to TNF-α and IL-8 signaling.[84] However, it also increased neutrophil lifespan via the p38 MAPK pathway. Overall, this intervention increased neutrophil-mediated inflammation.[84] Recently, however, it was found that one member of the NF-κB family, RelB, has anti-inflammatory activity, also in smoke-induced inflammation.[85,86] In murine studies, targeted overexpression of RelB lead to decreased CS-induced neutrophil inflammation of the lungs as well as decreased levels of proinflammatory cytokines and chemokines.[86] Therefore, current research is focused on understanding the specific features of RelB and the possibility of upregulating it as a method of intervention for COPD.[86]