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Page 8 of 14 Borek et al. Rare Dis Orphan Drugs J 2023;2:5 https://dx.doi.org/10.20517/rdodj.2022.20

Table 1. Studies investigating therapeutic modulation of serine proteases in preclinical models of PH
Target Inhibition strategy Preclinical PH model Main outcomes
NE Recombinant elafin S100A4/Mts1 overexpression Attenuation of the development of neointimal lesions [50]
(develop PA neointimal lesion)
-mice
Recombinant elafin SuHx-rats Improved hemodynamics and RV hypertrophy, regression of PA
[68]
occlusive changes
Elafin overexpression Chronic hox- mice Decreased severity of pulmonary vascular disease [69]
Inhibitors M249314 MCT-rats Reversal of established PAH with normalization of PA pressure and
and ZD0892 structure [70]
[75,76]
CtsG/PR3 Elafin has also been shown to modulate the activity of PR3
The specific role of CtsG/PR3 in PAH has not been addressed
[28]
Chymase Ketotife (MC stabilizer) MCT-rats Attenuation of PH and vascular remodeling
Tryptase MC Knock Out
Cromolyn (MC stabilizer) MCT-rats In preventive approach attenuated RVSP and decreased
[29]
c-kit inhibitor PLX muscularization
FSLLRY-amide Chronic hox-mice PAR-2 antagonist attenuated the development of PH and vascular
[31]
(PAR-2 antagonist blocks remodeling
tryptase-PAR2 axis)
Cromolyn (MC stabilizer) MCT + aortocaval shunt Lower chymase activity was associated with less advanced
TY-51469 (inhibitor) -rats pulmonary vascular remodeling and improved RV
[93]
hemodynamics
BCEAB (inhibitor) Bleomycin-induced PH due to lung Reduced pulmonary vascular remodeling and lung fibrosis, lower
[113]
fibrosis expression of TGFβ1 and MMP2 in PAs
-hamsters
Chymostatin (inhibitor) Cigarette smoke-induced COPD- Reduction of chymase activity and Ang II concentration in the lung.
PH-hamster Attenuated RVSP elevation and remodeling of pulmonary
[118]
arterioles
SuHx: Sugen 5416 + hypoxia rat model, MCT: monocrotaline rat model, chronic hox: chronic hypoxia mouse model, NE: neutrophil elastase, PR3:
proteinase 3, CtsG: cathepsin G.

Figure 1. Involvement of proteases in pulmonary arterial remodeling in PH. (A) Schematic representation of a healthy arterial wall. (B)
Arterial remodeling is accompanied by PASMC hyperplasia and ECM degradation and remodeling leading to the loss of vessel
architecture. Immune cell-derived serine proteases can hydrolyze ECM proteins and modulate the bioavailability of cytokines,
chemokines, and growth factors, thus regulating processes central to the development of vascular pathology. PAEC: Pulmonary arterial
endothelial cells, PASMC: pulmonary arterial smooth muscle cells, advFB: adventitial fibroblasts, ECM: extracellular matrix, NE:
neutrophil elastase, PR3: proteinase 3, CatG: cathepsin G. Graphical abstract has been created with BioRender.com.

is complicated by the incredible complexity of the serine protease family and the fact that these enzymes are