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).