V.I. Studies in chronic obstructive lung diseases and chronic
lung inflammation
Chronic obstructive lung diseases mainly include asthma and chronic
obstructive pulmonary disease (COPD). In a study of meta-analysis, Wei
and colleagues have reported that the utilization of GLP-1-based drugs
showed reduced trends in the risks of nine categories of respiratory
diseases, including pneumonia, asthma, and COPD. However, GLP-1 based
drug utilizations were shown to increase trends in interstitial lung
disease (104). In a recent retrospective cohort study, Foer and
colleagues compared rates of asthma exacerbations and symptoms between
patients with T2D and asthma prescribed GLP-1RAs and those prescribed
sodium-glucose cotransporter-2 (SGLT-2) inhibitors, or DPP-4 inhibitors,
or sulfonylureas, or basal insulin. They observed that patients
prescribed GLP-1RAs had lower counts of asthma exacerbation and
encounters for asthma symptoms after 6 months of the treatment (105). In
another human study, Mitchell and colleagues reported that GLP-1R is
expressed in both human eosinophils and neutrophils but the numbers were
reduced in allergic asthmatics (106). Their ex vivo study showed
GLP-1 analog decreased the expression of eosinophil-surface activation
markers, as well as IL-4, IL-8 and IL-13 produced by eosinophils (106).
IL-33, a member of the IL-1 family, is constitutively produced in
fibroblasts, endothelial cells, and epithelial cells of skin, lung, and
gastrointestinal tract (107). It is among crucial mediators of both
innate and adaptive immune responses induced by aeroallergens.
Genome-wide association studies (GWAS) have revealed the implication ofIL33 locus in the development of asthma (108, 109). To date,
there is no known therapeutical agent that can inhibit the release of
IL-33 from airway cells (110). When Alternaria extract, an
aeroallergen with protease activity, is intranasally administrated in
mice, acute asthma can be induced. In this mouse model, Toki and
colleagues assessed both “preventative” and “therapeutic” effects of
liraglutide. Either administrated before or after Alternariaextract challenge, liraglutide suppressed IL-33 secretion, associated
with decreased numbers of group 2 innate lymphoid cells (ILC2s), reduced
mucus production, and airway responsiveness (110). However, further
mechanistic explorations are needed for clarifying the involvement of
GLP-1R and the downstream signaling events. In another chronic asthma
mouse model challenged with ovalbumin for 81 days, i.p . injection
of liraglutide at 2mg/kg twice daily in the last 66 days inhibited
airway inflammation and mucus hyper-secretion through a protein kinase A
(PKA)-dependent signaling pathway (111).
COPD is among the top leading cause of death worldwide. Up to date, here
is no approved therapy that is able to reverse lung injury caused by
COPD. Huang and colleagues have reported that expression of GLP-1R in
PBMC isolated from COPD patients is lower than that in non-COPD subjects
(112). Ex vivo liraglutide treatment, however, upregulated GLP-1R
expression and restored antigen-stimulated interferon γ (IFN-γ)
production in T lymphocytes (112). Considering the intensive literature
controversy on GLP-1R expression in extra-pancreatic organs, further
investigations are needed for clarifying GLP-1R expression in immune
cells with newly developed GLP-1R antibodies and other tools such as
RNAseq (96, 100, 101, 113, 114). There is an on-going clinical trial
operated by Hospital South-West Jutland, University of Southern Denmark
on assessing effects of liraglutide treatment in patients with COPD.
This prospective, randomized, placebo-controlled, double-blinded,
parallel group two-center clinical trial, headed by Dr. Claus B Juhl,
will determine various pharmacological effects and functional outcomes
of 4-, 20-, 40- and 44- week liraglutide treatment in 40 patients with
COPD.
Pulmonary surfactant is a surface-active complex of proteins and
phospholipids formed by type II alveolar cells, which plays important
roles in regulating alveolar size and lung innate immunity, as well as
in preventing fluid accumulation and maintaining dryness of the airway.
In human type II pneumocytes isolated from cadaveric organ donors, Vara
and colleagues found that native GLP-1 or exenatide could stimulate cAMP
formation and phosphatidylcholine secretion; and such effects were shown
to be reversed by the GLP-1R antagonist exendin (9–39) (115). Early
investigations have generated ovalbumin and long-term LPS induced rodent
COPD models (116, 117). Combining these two models, Viby and colleagues
have assessed the effect of liraglutide on improving lung functions in a
female COPD mouse model (118). They found that mice treated with
liraglutide or exenatide showed much better clinical appearance and
increased survival rate. They also observed reduced expression of
surfactant proteins in their COPD female mouse model, associated with
increased expression of pro-inflammatory cytokines. However, levels of
surfactants and pro-inflammatory cytokines in the lung were largely
unaffected with liraglutide treatment in female COPD mouse model (118).
One may speculate that long-term (> 10 days) liraglutide
administration may exert more profound “metabolic” beneficial effects
in addition to its anti-inflammatory effect observed in the acute injury
model. Nevertheless, the stimulatory effect on surfactant secretion was
not observed in this in vivo model, in contrast with the in
vitro assay with human type II pneumocytes isolated from cadaveric
organ donors (115). Thus, mechanisms underlying the improvement effect
of liraglutide treatment in COPD is complicated, involving not only
surfactants and pro-inflammatory cytokines, but also other yet to be
identified components.
As mentioned above, Kim and colleagues have located mouse GLP-1R
expression in mouse cardiac atria and shown that GLP-1R activation
increased cardiac atria ANP secretion, leading to the reduction of blood
pressure (79). As an atrial natriuretic peptide hormone, ANP is also
recognized as a potent pulmonary vasodilator (119). Although ANP is
mainly produced in the heart, pulmonary ANP expression was reported, at
least in rodent species at its mRNA level (120). Utilizing the mouse
COPD model, Balk-Moller and colleagues have assessed lung function of
GLP-1-based drugs. Although mouse lung functions did not differ between
mice receiving PBS and exendin (9-39) (a GLP-1R antagonist) treatment,
or between GLP-1R knockout mice and their wild-type littermates, COPD
mice receiving GLP-1-based drugs (liraglutide or exenatide) showed
improved pulmonary functions, with less inflammation and 10-fold more
ANP at the mRNA level. In isolated mouse bronchial sections, direct ANP
treatment showed a moderate broncho-dilatory effect, while such effect
was also observed, although less effective, with direct liraglutide
treatment. Based on this finding, the authors suggested a link between
GLP-1 and ANP in COPD. Balk-Moller and colleagues, however, did not
assess pulmonary ANP production at peptide hormone level. Hence, it
remains to be determined whether observed beneficial effect of
liraglutide treatment is generated by ANP produced in cardiac atria
only, or with the contribution of pulmonary produced ANP (120).
Nosocomial infections especially that in the lung is a critical
complication world widely. Lung chronic infections can be generated by
respiratory pathogens including the most notorious pathogenPseudomonas aeruginosa (P. aeruginosa) . P. aeruginosa and
its virulence factor, known as pyocyanin, was shown to attenuate
expression of forkhead box A2 (FOXA2), a key transcription factor of a
battery of genes that are involved in mucus homeostasis (121). Choi and
colleagues have shown that FOXA2 expression was severely depleted in
surface airway epithelial cells in patients with COPD, while exenatide
treatment can restore FOXA2 expression in P. aeruginosachallenged mouse model (122).