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

PULMONARY ARTERIAL HYPERTENSION
Pulmonary arterial hypertension (PAH) is a severe clinical condition characterized by persistent elevation of
[1]
pulmonary arterial pressure (> 20 mmHg) . Even with the best standard of care, the overall prognosis for
PAH patients remains poor, with a 3-year mortality rate of 21%. The picture looks even worse for patients
[2]
from the high-risk PAH group with a 3-year mortality rate of 28%-55% . PH can develop as a primary
disease with an unknown cause (idiopathic, IPAH), as a result of the loss-of-function mutation in the gene
encoding the bone morphogenetic protein receptor type II (BMPR-2, heritable PAH), or in association with
[3]
other diseases . However, irrespective of the underlying cause, all pulmonary hypertension forms are
accompanied by progressive vascular remodeling , evident in small and medium size distal pulmonary
[4]
arteries (PAs). Narrowing of the vessel lumen, together with reduced vasodilatory capacity, results in an
increased pulmonary vascular resistance (PVR), progressively leading to right ventricle (RV) hypertrophy,
[5]
heart failure, and ultimately premature death . Pathogenesis of PAH is very complex and multifactorial and
consensus on what triggers the disease development is missing. Affected vessels show pulmonary arterial
endothelial cell (PAEC) dysfunction, expansion of media caused by abnormal proliferation of pulmonary
arterial smooth muscle cells (PASMC), and changes in the extracellular matrix (ECM) architecture with
collagen deposition and elastic lamina breakdown . Vessel remodeling is commonly accompanied by
[6]
[7]
perivascular inflammation and cumulative evidence suggests that active recruitment of immune cells and
inflammatory mediators, such as serine proteases, can drive pathogenic processes in PAH [8-10] . In this review,
we will focus on the role of aberrant inflammatory response and serine proteases-mediated vascular injury
in the initiation and propagation of PH-associated vasculopathy. We will also briefly discuss the utility of
serine protease targeting as a novel immunomodulatory, anti-remodeling treatment strategy in PH.

Immune dysregulation in PH
There is growing evidence that maladaptive immune response plays an important role in PAH
pathogenesis. The presence of several types of autoantibodies against vascular wall components has been
identified in PAH [11,12] . Inflammatory mediators, involved in the leukocyte recruitment and activation, are
elevated in the circulation and lungs of patients, and their increased levels correlate with worse clinical
outcomes (e.g., interleukins IL-1β, IL-2, IL-4, IL-6, IL-8, MCP1, CCL5, CX3CL1, and TNFα) [13-16] .
Furthermore, an increased prevalence of PH is observed in individuals suffering from diseases associated
with maladaptive immune responses, e.g., scleroderma, systemic lupus erythematosus, sarcoidosis, and
chronic obstructive pulmonary disease (COPD) [17-20] . In experimental PAH, inflammation proceeds the
development of vascular changes, suggesting its causal role in vascular remodeling [21,22] . Interestingly, single-
cell interaction mapping identified the remarkable breakdown of intracellular communication in diseased
vessels. While in healthy PAs, harmonious crosstalk between the immune and structural cellular
compartments can be observed, in PAH, there is a strong upregulation of ligand-receptor pairs between
[23]
PASMC and granulocytes . This indicates that in PAH, vascular cells enforce communication both within
the vessel and with the granulocyte compartment.

Endothelial dysfunction is believed to be one of the triggers initiating a detrimental process that ultimately
leads to vascular remodeling and evidence of an activated pulmonary endothelium is commonly found in
PAH patients . Increased expression of leukocyte adhesion molecules and inflammatory mediators by
[24]
endothelial cells provides a perfect gateway for the tissue accumulation of inflammatory leukocytes .
[25]
Immune cell aggregates appear to be associated with active arterial remodeling, and perivascular
inflammation score correlates with PA hyperplasia, pulmonary hemodynamics, and clinical outcome . The
[9]
role of specific immune cell types has been investigated in the context of PAH pathogenesis. However, only
recently has it been shown in the systematic analysis of human samples that in comparison to healthy
donors, IPAH patients have markedly changed global immune landscape both in the lung parenchyma and
the PAs [23,26] . A multitude of different cells implicated in the disease process in PAH underpins the