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Borek et al. Rare Dis Orphan Drugs J 2023;2:5 https://dx.doi.org/10.20517/rdodj.2022.20 Page 5 of 14

layer on endothelial cells, leading to endothelial injury and subsequently increased retention of leukocytes in
the vessel [62-64] . Elastase can also directly affect PAECs function and induce apoptosis and endothelial barrier
disruption [53,65,66] . In the vasculature, bone morphogenetic protein receptor type 2 (BMPR-2) plays an
important role in the suppression of inflammation and supports the maintenance of the endothelial barrier
function . Enzymatic activity of NE has been shown to downregulate BMPR-2 signaling and thus could be
[67]
[68]
involved in the perpetuation of inflammatory response in the vessels .
Several studies point to the utility of NE activity inhibition as a promising treatment strategy in PAH.
Transgenic animals with overexpression of NE inhibitor, elafin, are protected from chronic hypoxia-
induced PH. Compared to the control animals, they show improved hemodynamics and attenuated vascular
[69]
remodeling . Pharmacological inhibition of NE shows the same beneficial effects in different experimental
models of PH [50,68,70] . Evaluation of Elafin in the randomized, placebo-controlled, blinded, phase I clinical
trial is currently ongoing (ClinicalTrials.gov Identifier: NCT03522935).

Proteinase 3 (PR3)
PR3 is another granule-associated serine proteinase involved in neutrophilic inflammation. It has high
sequence homology to NE and exhibits similar substrate specificity. Like NE, PR3 can hydrolyze elastin and
other important ECM components. However, PR3 also has some unique properties, e.g., a substantial
amount of this protease is present on the neutrophil surface, bound to the cell membrane. Membrane
association increases even further in activated neutrophils . The role of PR3 in the pathogenesis of PAH
[71]
has never been specifically addressed. However, indirect evidence supports its involvement in the disease
process. In particular, PR3 can efficiently convert TNFα and IL1β to their bioactive forms and TNFα has
[72]
been shown to be a central driver of PAH. Out of several cytokines implicated in PAH, TNFα selectively
reduces the expression of BMPR-2 in PASMCS and PAECs , and deficiency of the BMPR-2 is a genetic
[73]
risk factor for the development of the hereditary form of PH . TNFα-induced alteration of BMP signaling
[74]
results in excessive proliferation of PASMCs , thus contributing to vascular hyperplasia. Of note, the
[73]
therapeutic effect of elafin in PAH could be reinforced by its ability to modulate also PR3 activity [75,76] .
Cathepsin G (CatG)
CatG shares its primary specificity with NE and PR3, and it is an essential component of neutrophil
granule-associated proteolytic machinery involved in a broad range of neutrophil functions. As in the case
of PR3, the role of CatG in PAH has never been directly addressed. However, many processes that play a
role in PAH pathogenesis, e.g., regulation of vascular tone, different aspects of the inflammatory response,
and tissue remodeling, are influenced by CatG activity.

CatG and NE can convert pro-chemerin into its bioactive form . There is growing evidence to suggest that
[77]
chemerin plays an important role in regulating energy metabolism, cardiovascular homeostasis, and
inflammatory response (reviewed by Macvanin MT, et al. ). Chemerin can induce the chemotaxis of
[78]
[79]
dendritic cells and macrophages and modulate angiogenesis . Notably, vascular cells express the
[78]
chemerin receptor, chemokine-like receptor 1 (CMKLR1), and Chemerin-CMKLR1 signaling has been
shown to contribute to endothelial dysfunction, increase apoptosis resistance, and induce proliferation and
motility of PASMCs [78,80] . Additionally, chemerin has been shown to potentiate the vasoconstrictive and
mitogenic action of endothelin 1 . PAH patients have increased serum levels of both chemerin and
[81]
[82]
endothelin 1 , possibly contributing to their commonly observed chronic vasoconstrictive state.
[83]
Furthermore, neutrophil membrane-bound Cathepsin G has a catalytic activity that can generate the
vasoactive hormone angiotensin II, a central component of the renin-angiotensin-aldosterone system
(RAAS) responsible for regulating blood pressure . Angiotensin II promotes vasoconstriction and
[84]
stimulates aldosterone release, which activates kidney sodium retention, leading to elevated blood pressure.