Neutrophils and Emerging Targets for Treatment in COPD
Neutrophils and Emerging Targets for Treatment in COPD
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.
Neutrophils secrete MMP-9 upon stimulation with IL-8 and TNF-α. Normally, macrophages form the main source of MMP-9 in the lungs, but in COPD this role is taken over by neutrophils. 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.
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, but in vivo studies suggested MMP-9 is not necessary for neutrophil migration through tissue. 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.
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. 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. 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. 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.
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. Normally, macrophages form the main source of MMP-9 in the lungs, but in COPD this role is taken over by neutrophils. 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.
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, but in vivo studies suggested MMP-9 is not necessary for neutrophil migration through tissue. 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.
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. 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. 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. 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.
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