3 Results
It has been shown that NE inhibition by sivelestat mitigate ALI through
amelioration of alveolar epithelium and vascular endothelium injuries as
well as reversing the activated neutrophil-mediated increased vascular
permeability (31). In a clinical study on patients with ARDS and
systemic inflammatory response syndrome, continuous infusion of
sivelestat has been shown to significantly improve pulmonary function,
as indicated by increased in PaO2/FIO2 ratio, shortened duration of
mechanical ventilation time and length of ICU care. However, the
mortality rate did not differ in comparison to control group (36). In
another clinical (phase III double blinded) trial with 230 ALI patients,
sivelestat was shown to increase recovery rates of the pulmonary
functional parameters, reduced the duration of mechanical ventilator and
better weaning rates, and shortened ICU length of stay by almost half.
However, this selective NE inhibitor was not able to reduce 30-day
survival rate. In this study, only around 20% of death occurred due to
respiratory failure. This may explain why survival rate between the two
arms of the study did not reach a significant value (37).
There are several studies indicating that sivelestat increases
ventilator-free days and survival in patients with ALI/ARDS by
inhibition of the overstretch-induced signaling pathway and neutrophil
chemotaxis (38-40). During mechanical ventilation (MV), the risk of ALI
is increased due to over-activation of neutrophil elastase and
myeloperoxidase. Furthermore, phosphorylation of c-Jun NH2-terminal
kinase (JNK) is increased in alveolar type 2 epithelial cells (41).
There is a direct relationship between inhibition of JNK and prevention
of over-ventilation lung injury. JNK is also critical in induction of
apoptosis during stress responses (42). The protective effects of
sivelestat against MV was evaluated in animal model of mice where
sivelestat (100 mg/kg, intraperitoneally) or saline was administered 30
minute before ventilation. Under 4 hours of MV with high tidal volume of
20 mL/kg, sivelestat prevented histopathological MV induced-lung damage,
decreased lung tissue wet to dry weight ratio, and suppressed the serum
and bronchoalveolar lavage fluid levels of macrophage-inflammatory
protein 2 (MIP-2), IL-6 and TNF-α. By inhibition of neutrophil
chemotaxis, sivelestat also normalized the phosphorylation level of JNK
and attenuated apoptotic changes in pneumocytes after the MV-induced ALI
(43).
In a retrospective study of sivelestat in 110 patients with ALI and
sepsis, sivelestat significantly increased the number of ventilator free
days and PaO2/FIO2, especially in those patients with baseline
procalcitonin levels of ≥ 0.5 ng/mL (40). In another multicenter,
prospective study using 164 mechanically ventilated ARDS patients with
high wet-to-dry lung weight ratio, the efficacy of sivelestat was
compared to the control group. In this study, sivelestat increased
ventilator-free days with no significant effect on 28-day mortality
(39).
In a phase IV open-label, non-randomized, multi-center clinical trial
for the treatment of ALI associated with SIRS on 581 patients,
sivelestat was continuously administered intravenously at a dose of 0.2
mg/kg/h for 2 weeks. The results of this study showed a significant
higher ventilator-free day, ICU discharge rate and early weaning from
mechanical ventilator with sivelestat compared to control group.
Furthermore, those patients received sivelestat had a substantially
higher 180-day survival than control patients. The results of this
clinical trial emphasized on the clinical efficacy of this NE inhibitor
in this group of patients (44).
During ARDS and cytokine storm, the serum levels of TNF-α, IL-6, high
mobility group box 1 (HMGB1) protein, and NO synthesis from iNOS, which
contribute to the host’s inflammatory responses, rise significantly
(45-47). As indicated in the preceding texts, the NF-κB signaling
pathway regulates the expression of these inflammatory factors (48, 49).
Furthermore, NE-mediated chemotaxis to the lung potently induces
epithelial cells to produce inflammatory cytokines and macrophages to
MCP-1 (50). It has been demonstrated that sivelestat decreases NF-κB
pathway stimulation, and inhibits the secretion of HMGB1 from
macrophages through inhibition of IκB kinase phosphorylation (51).
Moreover, the serum levels of TNF-α, IL-6, HMGB1, and NO were shown to
significantly decrease following administration of sivelestat. This
selective NE inhibitor could also substantially reduce the level of
MCP-1 mRNA in macrophages during ischemia-reperfusion injury (52).
As outlined above, COVID-19 patients are more susceptible to
thromboembolic diseases including DIC. In this connection, various
studies have emphasized on the role of NE in the development of DIC in
patients with ARDS and sepsis. In a study on 167 septic patients with
ARDS and DIC, sivelestat was administered upon admission to ICU and
continued for 5 days. The results showed that sivelestat improved lung
injury score, PaO2/FIO2 ratio, DIC score, and ICU length of stay and
survival rate when compared to the control group (53).
In another study on 142 ARDS patients with DIC, the efficacy of
sivelestat alone, recombinant human soluble thrombomodulin (rhTM) alone,
combination therapy of sivelestat and rhTM or untreated control were
evaluated and compared to each other. The results were very promising,
indicating that combination therapy with sivelestat and rhTM
significantly increased the 60-day patient survival, mechanical
ventilator-free days, and better PIO2/FIO2 ratio and DIC score (54).