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Page 6 of 10 Zierke et al. Rare Dis Orphan Drugs J 2023;2:10 https://dx.doi.org/10.20517/rdodj.2022.17

Figure 1. Roles of lysosomal and neutrophil serine proteases in acute pancreatitis. The conversion of trypsinogen into its active form is an
important step in the early phase of acute pancreatitis. In addition to autoactivation, trypsinogen is activated by cathepsin B (CTSB)
derived from acini and macrophages. Pro-CTSB itself is proteolytically activated by cathepsin D (CTSD). While cathepsin C (CTSC) does
not directly act on trypsinogen, it activates the neutrophil serine proteases cathepsin G (CTSG), proteinase 3 (PR3), and neutrophil
elastase (NE). NE readily cleaves the cell-adhesion molecule E-cadherin, leading to the dissociation of acini.

Regarding type 2 AIP, one study compared pancreatic tissue samples of patients with alcoholic chronic
pancreatitis, type 1 AIP, and type 2 AIP, and investigated the extent and localization of neutrophilic
infiltration. In addition, these authors analyzed the expression of the chemokines interleukin-8 (IL-8) and
granulocyte chemotactic protein 2 (GCP-2), both of which can bind to neutrophilic ELR CXC receptors
+
and can attract and activate neutrophils. In type 2 AIP, there was higher infiltration of neutrophils into the
interlobular ducts and the surrounding tissue, which was absent around the intralobular ducts. In addition,
the authors found higher expression of GCP-2 around the interlobular but not around the intralobular
ducts, and levels of IL-8 expression remained unaltered. They concluded that the increase of neutrophilic
infiltration into the interlobular ducts in type 2 AIP depends on GCP-2 which is secreted by pancreatic
epithelial cells .
[70]

Further knowledge of the role of neutrophils and NSPs in these two rare forms of pancreatitis remains
missing. Especially regarding type 2 AIP, knowledge of the interplay between the pancreas, infiltrating
neutrophils, and NSPs would be helpful for a more comprehensive understanding of this rare disorder.

MODULATION OF NEUTROPHIL SERINE PROTEASE ACTIVITY
Because NSPs are involved in the pathophysiology of acute pancreatitis, their inhibition is of therapeutic
interest. Increased NE activity or an imbalance with endogenous inhibitors can cause a broad range of
diseases apart from pancreatitis. Existing NE inhibitors with high inhibitory capacities and low cytotoxicity
[71]
in vitro have not only been isolated from animal sources and fungi but have also been designed
synthetically, thus providing a strong basis for subsequent clinical investigations. The most prominent
[72]
synthetic compound, AZD9668, has been reported to show beneficial effects in chronic lung diseases .