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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 7 of 14

[108]
embryonically lethal . Chymase can modulate inflammatory response by modification of cytokines and
[109]
chemokines, e.g., IL-1β, IL-18, and CXCL7 . Moreover, it participates in ECM degradation and
remodeling, either via direct cleavage of proteins such as fibronectin or by activation of other enzymes,
[110]
e.g., MMP-2 and MMP-9 [111,112] . Investigation of the role of chymase in pulmonary hypertension
pathogenesis confirmed the utility of chymase targeting as a promising therapeutic approach. In
comparison to controls, inhibitor-treated animals showed improved hemodynamics and significantly
reduced vascular remodeling. Decreased chymase activity resulted in lower levels of TGF-β1 and MMP-2, as
well as diminished endothelin 1-mediated pulmonary vasoconstriction , providing hints into the
[113]
mechanism behind the protective effect mediated by chymase inhibition.

OTHER SERINE PROTEASES
Serine proteases are a diverse family of proteolytic enzymes expressed not only in neutrophils and mast cells
but also in other granulocytes, such as eosinophils and basophils. The role of eosinophils in PH is complex
and context-dependent, as they have been implicated in both promoting and preventing the
[115]
[114]
development of this condition. Animal models of pulmonary arterial hypertrophy have shown that
[116]
depletion of eosinophils using anti-IL-5Rα antibodies can ameliorate vascular remodeling , and patients
with eosinophilic COPD are at a 7-fold increased risk of PH compared to non-eosinophilic COPD . These
[117]
findings suggest a potential role for eosinophil-derived mediators in the pathogenesis of pulmonary
hypertension. However, it is not yet clear whether eosinophil-derived serine proteases specifically contribute
to this effect.

Basophil accumulation has also been observed in the lungs and pulmonary arteries of IPAH patients .
[26]
Basophils share many characteristics with mast cells, and it is possible that mast cell-targeted therapies exert
their effects, at least in part, via modulation of basophil function. However, the specific role of basophils in
pulmonary hypertension remains unclear. Most of the evidence to date supports the involvement of
neutrophil-derived NSPs and MC-derived tryptase and chymase in the pathogenesis of PAH. However, it is
important to consider that other serine proteases may also participate in the pathological processes
underlying this disease, and further research is needed to fully elucidate their roles.

A summary of preclinical studies addressing anti-serine protease strategies in PH treatment can be found in
Table 1.

CONCLUDING
There is an urgent need for the identification and development of novel therapeutic strategies for PAH, as
current treatments target primarily vasoconstriction rather than vasculopathy which underpins the
pathology of this disease. Vasodilators ameliorate the symptoms, improve functional capacity and reduce
hospitalizations, but do not protect patients from the development of progressive, occlusive vascular lesions
and clinical deterioration [44,119] . Growing evidence supports the notion that dysregulated immunity and
increased immune-cell-derived proteolytic activity play a central pathogenic role in the development and
progression of vessel remodeling and PAH (summarized in Figure 1). Experimental models showed that
inhibition of selected serine proteases, such as NE or chymase, can prevent, or in some instances even
revert, vascular remodeling and disease progression [70,113] . Therefore, a strategy that modulates the effects of
the aberrant activity of immune cell-derived proteases to reduce inflammation and preserve the structural
integrity of the vessel wall holds great therapeutic promise. The development of anti-serine protease therapy
is a rapidly advancing field of research. Despite significant efforts, designing an effective strategy has proven
to be challenging. The multifaceted regulation of serine protease activity provides many targeting
opportunities, but it also makes the design of an effective drug difficult. Furthermore, therapeutic targeting