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

Protease Imbalance

Once the neutrophils have accumulated, they secrete many factors that are harmful to the lungs. Perhaps the best-studied component of COPD is an imbalance of the protease–antiprotease ratio. An insufficient inhibition of proteases seems to be a key factor in the pathogenesis of this disease. This is illustrated by patients with a deficiency of A1AT, an inhibitor of NE, which, as mentioned before, develops COPD as a genetic disease. Besides an NE imbalance, an imbalance of MMP-9, as one of the metalloproteases capable of degrading structural components of the extracellular matrix, seems to be a main instigator. This section will discuss what is known about the role of these two proteases in the etiology of COPD.

MMP-9

Neutrophils secrete MMP-9 upon stimulation with IL-8 and TNF-α.[87,88] Normally, macrophages form the main source of MMP-9 in the lungs, but in COPD this role is taken over by neutrophils.[89] The concentration and activity of MMP-9 correlates with disease severity. Normally, MMP-9 is released in a MAPK-dependent fashion but in COPD patients inhibition of this pathway does not affect neutrophilic MMP-9 release, although it did affect MMP-9 release by macrophages.[90]

The exact function of neutrophil-released MMP-9 in COPD, or in normal physiology, for that matter, remains to be elucidated. It has been suggested MMP-9 would facilitate neutrophil migration to the site of inflammation,[49] but in vivo studies suggested MMP-9 is not necessary for neutrophil migration through tissue.[91] Inhibition of MMP-9 did not affect neutrophil influx in an inflammatory lung model and MMP-9−/− mice showed no significant decrease in neutrophil counts in BAL fluids.[92,93]

The activity of MMP-9 is regulated by tissue inhibitor of matrix metalloproteases 1 (TIMP-1). In COPD, the ratio MMP-9/TIMP-1 is markedly changed and correlates positively with disease severity.[94] Though this correlation between MMP-9 activity and COPD severity has been well established, the mechanisms by which MMP-9 exerts its effects are yet to be elucidated. In idiopathic pulmonary fibrosis the MMP-9/TIMP-1 ratio was unrelated to disease progression and severity.[88] This suggests that the MMP-9/TIMP-1 imbalance correlates with COPD severity due to its role in emphysema and/or bronchiolitis, rather than affecting the fibrotic element of COPD. Still, its general proteolytic activity and its strong capability to degrade extracellular matrix components such as elastin are widely accepted to play a role and it has been suggested that breakdown of collagen may, via the degradation products, lead to enhanced neutrophil activation.[95] Furthermore, it has been suggested that aggravation of COPD might be due to an increased inflammatory burden, due to an additional infection, coinciding with an MMP-9/TIMP-1 imbalance.[96]

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