Teduglutide, a glucagon-like peptide 2 analogue: A novel protective agent with anti-apoptotic and anti-oxidant properties in mice with lung injury
Highlights
► TNF-α treatment combined with Act D makes the lung a vulnerable sensitive organ to damage. ► We demonstrated here for the first time the localization of GLP-2 receptors in the lung. ► Teduglutide is as a novel protective agent with anti-apoptotic and anti-oxidant properties against acute lung injury.
Introduction
Glucagon-like peptide-2 (GLP-2) is a proglucagon-derived peptide hormone which has trophic effects on the small and large intestine epithelium. GLP-2 is rapidly inactivated by dipeptidylpeptidase IV in circulation, therefore dipeptidylpeptidase IV-resistant synthetic analogues of human GLP-2 such as teduglutide, h[Gly2]GLP-2, is often used in animal studies [46]. Administration of GLP-2 or its analogues promotes intestinal recovery and enhances epithelial repair by stimulating the proliferation of epithelial cells and by reducing apoptosis in several experimental models of intestinal injury including short bowel syndrome [27], inflammatory bowel diseases [8], enteritis [51], and TNF-α/Act D-induced intestinal damage [3]. Sinclair and Drucker noted that the actions of GLP-2 occur through binding to a single G protein-coupled GLP-2 receptor (GLP-2R) [1]. GLP-2R mRNA transcripts have been detected in the stomach, small and large bowel, brain, and lungs of rodents and humans [61].
Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine produced by various cell types such as activated macrophages, monocytes, lymphoid cells, endothelial cells and fibroblasts. It plays a significant role in the pathogenesis of many inflammatory lung diseases including acute lung injury, acute respiratory distress syndrome, asthma, chronic bronchitis and chronic obstructive pulmonary disease [21], [23], [39], [55]. TNF-α is known to be involved in the signaling mechanisms of cellular proliferation, survival, immunity, apoptosis and inflammation [39]. High concentrations of TNF-α can stimulate cytotoxicity and cell death by promoting inflammatory and prooxidative responses in the lung, liver, and intestine [3], [33], [39]. The proapoptotic effect of TNF-α is strongly enhanced when neosynthesis of protective proteins is blocked by transcriptional inhibitors. Actinomycin D (Act D), a transcriptional inhibitor, is one of the anti-neoplastic drugs that induces tissue damage via the depletion of nucleotides and subsequently reduces RNA and protein synthesis. Due to its properties, Act D has been widely used with TNF-α in in vitro studies in order to stimulate apoptotic cell death and markedly increase the cytotoxic effect of TNF-α [29], [33].
TNF-α-induced signal transduction pathways in lung cells are not completely understood. Moreover, there is a need to find new and effective agents for the improvement and adequate/appropriate repair of lung injury in the lung diseases mediated by TNF-α. The in vivo mouse model of lung injury induced by TNF-α/Act D has not been used until today, and also role of teduglutide on this novel model and other animal models for the lung disorders has not been tested yet. In this study, we aimed to investigate potential cytoprotective and reparative roles of teduglutide in lung injury induced by TNF-α/Act D in mice.
Section snippets
Animals and experimental design
In this study, 8- to 10-week-old male BALB/c mice (n = 48) from Experimental Medical Research Institute of Istanbul University were used. The experiments were reviewed and approved by the Animal Care and Use Committee of Istanbul University. The animals were fed with Purina Laboratory Rodent Diet 5001 and tap water ad libitum, but fasted for 16 h prior to the experiments. The animals were randomly divided into six groups. Group I (n = 7): control animals injected with 0.1% dimethyl sulfoxide (DMSO)
Histology
Healthy mice lung exhibited normal tissue structure. Administration of TNF-α/Act D caused a destruction of alveolar wall and thinning in some areas when compared with the control animals. This damage was more effective in mice lung treated with TNF-α/Act D than the groups treated only with TNF-α or Act D. In addition, these groups of mice have partly disintegrated alveolar walls. On the other hand, teduglutide pretreatment regressed the damage on the alveolar wall in the TNF-α/Act D-induced
Discussion
TNF-α plays an active role in the induction of cellular inflammatory reactions, enhancement of oxidative stress and expression of various proinflammatory mediators as well as adhesive molecules [32], [39]. It is taken up by lung after systemic release and causes lung injury [37]. Clinical observations and experiments conducted on animals have shown acute injury accompanied by noncardiogenic pulmonary edema, pulmonary inflammation and severe systemic hypoxemia in the lung possessing high levels
Conclusion
In the current study, we found that (1) TNF-α treatment combined with Act D makes the lung a sensitive organ to damage; (2) mice lung subjected to combined treatment with TNF-α/Act D were characterized by the disruption of alveolar wall, the induction of pulmonary endothelial/epithelial cell apoptosis, MPO activity and oxidative stress in addition to the reduction of TF and Na+–K+–ATPase activities; (3) teduglutide pretreatment given to mice that received TNF-α/Act D combination regressed the
Conflict of interest
The authors declare that they have no conflict of interest to disclose.
Acknowledgement
This work was supported by a Research Found from Istanbul University. Project no. UDP/2644/20062008.
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