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Page 4 of 12 Chen et al. Rare Dis Orphan Drugs J 2022;1:15 https://dx.doi.org/10.20517/rdodj.2022.18

in the localised areas halting their migration into the airways, and hence causing more localised tissue
damage. Furthermore, after degranulation, proteinases can become bound to neutrophil cell membranes
[32]
(especially in AATD ) and remain active while being resistant to AAT inhibition, which further
complicates the control of local proteinase activity, especially for AATD individuals.

The role of neutrophil elastase in the pathophysiology of emphysema is widely recognised. However,
emerging evidence suggests that Proteinase 3 may play a greater role in driving emphysema in AATD.
Proteinase 3 is stored at 3-4 times greater concentrations in the azurophilic granule than neutrophil
[33]
elastase . In addition to replicating pathological changes similar to emphysema in animals [26,34,35] ,
mathematical modelling indicated that Proteinase 3 possessed a greater potential for injury than neutrophil
elastase diffusing over a greater radius for longer before reaching an enzyme inhibitor equilibrium,
[23]
especially in AATD . Neutrophils from AATD subjects also expressed more Proteinase 3 on the cell
membrane , which is replicated by treating healthy neutrophils with deficient Z as opposed to normal M
[32]
AAT plasma, suggesting that AAT itself modulates cell membrane localisation.

An additional factor influencing the role of Proteinase 3 is that SLPI (the predominant antiproteinase in
airway secretion) is a poor inhibitor of Proteinase 3 and suggests that Proteinase 3 likely has a more
important role in tissue destruction, especially in AATD [22-24] . This is supported by the persistent Proteinase
3 activity in lung secretions of AATD patients compared to those with non-deficient chronic obstructive
pulmonary disease (COPD) even when elastase activity is undetectable [32,36] and the greater plasma
concentrations of the Proteinase 3 activity footprint than that of the neutrophil elastase footprint as
[37]
measured by the specific fibrinogen cleavage products .
Neutrophils and emphysema
Neutrophil serine proteinases, particularly neutrophil elastase and Proteinase 3 are essential to neutrophil
migration through the lung interstitium [24,38] . The movement of neutrophils is facilitated by the mobilisation
of proteinases to the leading edge of the cell . During this process, the concentration of the released
[39]
proteinases in the pericellular space overwhelms their inhibitors, causing an area of obligate destruction
closely surrounding the neutrophils until the proteinases diffuse away and an equilibrium is reached [24,32] . In
AATD, the destructive effect is amplified as cell surface proteinases are less controlled, potentially causing a
greater area of damage .
[40]
Accumulation of neutrophils in the lung is well documented in AATD. This neutrophilic accumulation is in
response to locally released chemoattractants. Leukotriene B4 (LTB4) is generated and released by alveolar
macrophages in response to excess neutrophil elastase activity . Similarly, CXCL8 can be released from
[41]
epithelial cells in response to an elastase challenge . Both these potent chemoattractants have been detected
[42]
at high levels in lung secretions of AATD . Additionally, tissue degradation products generated by elastase
[43]
from elastin can also add to the chemoattractant signal gradient , providing an amplification loop to the
[44]
lung neutrophilic response, thus enhancing tissue damage.
Understanding the whole pathway involved in tissue damage in AATD (See Figure 1) provides a series of
potential therapeutic interventions to restore a physiological balance and protect the lung.

With this whole pathway in mind, there are several defined points at which the process can potentially be
modulated.