V.II. Studies in acute lung injury
Acute lung injury (ALI) may lead to the development of acute respiratory
distress syndrome (ARDS) which is the major cause of respiratory failure
in ICU. To our knowledge, GLP-1-based drugs have not been utilized in
clinical trials for ALI. Nevertheless, as mentioned above, a very recent
retrospective study has shown that the utilization of GLP-1 based drugs
reduced trends in the risks of pneumonia, in addition to asthma and COPD
(104). Intensive investigations have, however, been conducted in ALI
animal models, mainly with intratracheally LPS administration in mice
(123).
In 2011, Lim and colleagues have developed a “nanomedicine” designated
as GLP1-SSM, in which human GLP-1 (7-36) is self-associated with
PEGylated phospholipid micelles (SSM). They then demonstrated that in
LPS induce ALI mouse model, subcutaneous GLP1-SSM administration
decreased lung neutrophil influx, myeloperoxidase activity and IL-6
levels in a dose-dependent manner (124). In 2017, GLP-1-SSM was shown by
this team to alleviate gut inflammation in a dextran sodium sulfate
induced mouse colitis model (125).
Several recent studies have explored mechanisms underlying the
attenuating effect of GLP-1R agonists in ALI animal models. Reduction of
pulmonary surfactant is tightly associated with decreased pulmonary
compliance and edema in ALI. Thyroid transcription factor-1 (TTF-1) is
known to play an important role in regulating levels of surfactant
protein-A (SP-A), the most abundant protein component of pulmonary
surfactant. Romaní-Pérez and colleagues have reported that in rats,
administering of exenatide or liraglutide to the mother from gestational
day 14 to the birth increased SP-A and SP-B mRNA levels and the amount
of SPs in the amniotic fluid at the end of pregnancy (126). Furthermore,
they have reported that lung GLP-1R mRNA level increased 4-fold at the
1st day of life in both male and female rats, while
the level of expression was subsequently maintained into the adulthood
(126). In 2018, Zhu et al found that in the ALI mouse model, LPS
administration reduced lung SP-A and TTF-1 levels, while the reduction
was reversed by simultaneous administration of liraglutide with LPS
challenge (127). In 2019, in a similar mouse model, Xu and colleagues
found that LPS challenge induced polymorphonuclear neutrophil (PMN)
extravasation, lung injury, along with alveolar-capillary barrier
dysfunction. Concomitant liraglutide administration prevented
PMN-endothelial adhesion by inhibiting expression of intercellular
adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1
(VCAM-1) (128). Other documented functions of GLP-1-based drugs in ALI
models include the stimulation of eNOS/sGC/PKG signalling cascade, the
induction of vasorelaxant expression, and the inactivation of the NF-κB
inflammatory signalling (129-131). However, none of these investigations
have directly assessed the involvement of pulmonary GLP-1R.
In 2020, our team has directly assessed the involvement of GLP-1R in
mediating effect of liraglutide treatment in LPS-induced ALI mouse
model. In this study, conducted by Zhou and colleagues, liraglutide was
not administrated simultaneously with LPS challenge, but as a
“preventative agent” which was subcutaneously administrated 2 hours
before intratracheal LPS delivery (103). In such experimental settings,
we observed that liraglutide pre-treatment significantly reduced
LPS-induced acute lung injury, including the reduction on lung injury
score, wet/dry lung weight ratio, immune cell counts, protein
concentration in bronchoalveolar lavage fluid (BALF), and cell apoptosis
in the lung. Those effects were highly associated with reduced pulmonary
mRNA expression of genes that encode inflammatory chemokines and
cytokines. Importantly, none of those “preventative” effects were
observed in GLP-1R knockout (KO) mice, highlighting the essential role
of lung GLP-1R in mediating the effect of liraglutide in preventing lung
injury (103). Based on such “preventative” effect observed, we
suggested that retrospective studies should be conducted in T2D subjects
received with or without GLP-1 based drugs, asking whether T2D patients
are less vulnerable to ALI as well as chronic lung inflammatory injury
after receiving GLP-1 based drug treatment (103, 132, 133).
The study conducted by Zhou and colleagues has also revealed that
liraglutide treatment attenuated LPS induced pulmonary
thioredoxin-interacting protein (TxNIP) over-expression, and such
attenuation is also GLP-1R dependent (103). TxNIP is a member of the NLR
family pyrin domain containing 3 (NLRP3) inflammasome component
(134-136), a mediator of glucotoxicity (137, 138), and a therapeutic
target of T2D and other disorder (135, 138-141). In addition to high
glucose challenge, TxNIP level in pancreatic β-cells was also shown to
be stimulated by dexamethasone and streptozotocin (STZ), an antibiotic
utilized in generating the T1D rodent model. Importantly, LPS challenge
caused approximately 2.5-fold elevation in lung TxNIP levels in wild
type littermates, while in GLP-1R KO mice, lung TxNIP increased about
7-fold after the challenge with the same amount of LPS. Thus, lung
GLP-1R itself may represent a native defensing system. In contrast to
the observation made by Balk-Moller and colleagues in their COPD model,
we did not see a stimulatory effect of liraglutide treatment on
pulmonary nppa (which encodes ANP) expression (120). However, we
observed that LPS challenge led to a 3-fold activation on pulmonarynppa level. Whether such activation represents a protective or
defensive response remains to be further explored (103). Figure 3
summarizes our current understanding on pulmonary GLP-1R mediated
protection in ALI mouse model, in response to GLP-1R agonist treatment,
involving the attenuation of the inflammasome component TxNIP.