Neutrophils and Emerging Targets for Treatment in Chronic Obstructive Pulmonary Disease

Mariska Meijer; Ger T Rijkers; Frans J van Overveld

Disclosures

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

In This Article

Neutrophil Elastase

In COPD patients, the genes for proteinase-3, cathepsin-G and NE, which together form the NSPs are upregulated.[68] Of these, the proteolytic and proinflammatory NE plays the most important role in COPD. It is a major predictor of disease severity, especially of the emphysematous component of COPD.[62,97] This would be expected, as NE concentrations are a measure of neutrophil infiltration. However, other measures, such as FEV1, suggest NE plays a role in the progression of the disease.

Normally, NE is mainly expressed on the cellular membrane with only 5% being released into the extracellular environment.[98] However, in COPD much more NE becomes available extracellularly, possibly because of the increased amount of necrotic neutrophils present.[62,99] Normally, the presence of NE on the extracellular membrane is tightly regulated by the degree of neutrophil activation. For NE to be secreted, tight contact with a pathogen must be established via numerous adhesion molecules, thus ensuring that the proteolytic activity of NE is contained to the area where it is required.[99] However, in COPD the conditions in the airway lead to neutrophil necrosis which in turn leads to an excessive and uncontrolled secretion of NE into the environment.[99] This was actually found in BAL fluid of severe COPD patients, with the highest NE activity in GOLD IV patients.[100] The proteolytic and proinflammatory properties of NE would thereafter contribute to a significant portion of the histopathology found in COPD and the recruitment of inflammatory cells.

One of the ways by which the proteolytic activity of NE becomes damaging, is by its degradation of TIMP-1 and activation of pro-MMP-9.[62,101] In addition, NE is a very potent inducer of mucous gland hyperplasia, one of the characteristics of emphysema.[62,99,102] Even so, as mentioned before, the emphysema severity did not correlate with gland mass very well, so by itself this does not explain the effect of NE on COPD. Second, like MMP-9, NE has potent proteolytic activity, capable of destroying bacteria, as well as degrading of extracellular matrix components such as elastin and therefore it can play a role in the airway remodeling that is found in COPD.[62,103]

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