Abstract
Acute lung injury (ALI) is an urgent disease lacking effective therapies, resulting in relatively high morbidity and mortality. The pathological mechanism of ALI is reported to be related to excessive inflammation and activated oxidative stress. The present study aims to investigate the protective effects of the DPP-4 inhibitor Trelagliptin against lipopolysaccharide (LPS)-induced ALI and the underlying mechanism. LPS was used to induce ALI mice models. The pathological condition of ALI mice was evaluated using MPO activity assay, lung wet to dry weight ratio detection, and HE staining on the lung tissues. Lung function was assessed using a spirometer. The oxidative stress level in the lung tissues was checked by MDA measurement and GPx detection using commercial kits. The leukocyte and neutrophil numbers were determined using a hemocytometer and the total concentration of protein in the BALF was detected using a bicinchoninic acid method. The expression levels of TNF-α, IL-6, and CXCL2 in the lung tissues were evaluated using qRT-PCR and ELISA. Western blot analysis was used to determine the expression levels of TLR4 and p-NF-κB p65. LPS-induced elevated MPO activity, pulmonary wet to dry weight ratio, airway resistance (RAW), the total number of leukocytes and neutrophils, production of inflammatory factors, decreased pulmonary dynamic compliance (Cdyn), and peak expiratory flow (PEF), and an aggravated histopathological state (such as disordered alveolar structure, significant pulmonary interstitial edema, and large numbers of red blood cells and inflammatory cells in the alveolar cavity) were significantly reversed by the administration of Trelagliptin. The TLR4/NF-κB signaling pathway was activated and oxidative stress was induced by stimulation with LPS; however, both effects were suppressed by the administration of Trelagliptin. Trelagliptin might alleviate LPS-induced inflammation and oxidative stress in acute lung injury mice.
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Ashbaugh, D.G., D.B. Bigelow, T.L. Petty, and B.E. Levine. 1967. Acute respiratory distress in adults [J]. Lancet 2 (7511): 319–323.
Rubenfeld, G.D., E. Caldwell, E. Peabody, J. Weaver, D.P. Martin, M. Neff, E.J. Stern, and L.D. Hudson. 2005. Incidence and outcomes of acute lung injury [J]. The New England Journal of Medicine 353 (16): 1685–1693.
Peter, J.V., P. John, P.L. Graham, J.L. Moran, I.A. George, and A. Bersten. 2008. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis [J]. BMJ 336 (7651): 1006–1009.
Iwata, K., A. Doi, G. Ohji, H. Oka, Y. Oba, K. Takimoto, W. Igarashi, D.H. Gremillion, and T. Shimada. 2010. Effect of neutrophil elastase inhibitor (sivelestat sodium) in the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): a systematic review and meta-analysis [J]. Internal Medicine 49 (22): 2423–2432.
Paine, R., 3rd, T.J. Standiford, R.E. Dechert, M. Moss, G.S. Martin, A.L. Rosenberg, V.J. Thannickal, E.L. Burnham, M.B. Brown, and R.C. Hyzy. 2012. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury [J]. Critical Care Medicine 40 (1): 90–97.
National Heart L, Blood Institute A C T N, J.D. Truwit, G.R. Bernard, J. Steingrub, M.A. Matthay, K.D. Liu, T.E. Albertson, R.G. Brower, C. Shanholtz, P. Rock, I.S. Douglas, B.P. de Boisblanc, C.L. Hough, R.D. Hite, and B.T. Thompson. 2014. Rosuvastatin for sepsis-associated acute respiratory distress syndrome [J]. The New England Journal of Medicine 370 (23): 2191–2200.
Anzueto, A., R.P. Baughman, K.K. Guntupalli, J.G. Weg, H.P. Wiedemann, A.A. Raventos, F. Lemaire, W. Long, D.S. Zaccardelli, and E.N. Pattishall. 1996. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group [J]. The New England Journal of Medicine 334 (22): 1417–1421.
National Heart L, Blood Institute acute respiratory distress syndrome clinical trials N, M.A. Matthay, R.G. Brower, S. Carson, I.S. Douglas, M. Eisner, D. Hite, S. Holets, R.H. Kallet, K.D. Liu, N. MacIntyre, M. Moss, D. Schoenfeld, J. Steingrub, and B.T. Thompson. 2011. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury [J]. American Journal of Respiratory and Critical Care Medicine 184 (5): 561–568.
Dellinger, R.P., J.L. Zimmerman, R.W. Taylor, R.C. Straube, D.L. Hauser, G.J. Criner, K. Davis Jr., T.M. Hyers, and P. Papadakos. 1998. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group [J]. Critical Care Medicine 26 (1): 15–23.
Fan, E., D. Brodie, and A.S. Slutsky. 2018. Acute respiratory distress syndrome: advances in diagnosis and treatment [J]. JAMA 319 (7): 698–710.
Gajic, O., O. Dabbagh, P.K. Park, A. Adesanya, S.Y. Chang, P. Hou, H. Anderson 3rd, J.J. Hoth, M.E. Mikkelsen, N.T. Gentile, M.N. Gong, D. Talmor, E. Bajwa, T.R. Watkins, E. Festic, M. Yilmaz, R. Iscimen, D.A. Kaufman, A.M. Esper, R. Sadikot, I. Douglas, J. Sevransky, M. Malinchoc, and U.S.C. Illness. 2011. Injury Trials Group: Lung Injury Prevention Study I. Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study [J]. American Journal of Respiratory and Critical Care Medicine 183 (4): 462–470.
Thompson, B.T., R.C. Chambers, and K.D. Liu. 2017. Acute respiratory distress syndrome [J]. The New England Journal of Medicine 377 (6): 562–572.
Han, S., and R.K. Mallampalli. 2015. The acute respiratory distress syndrome: from mechanism to translation [J]. Journal of Immunology 194 (3): 855–860.
Yan, X., X. Fu, Y. Jia, X. Ma, J. Tao, T. Yang, H. Ma, X. Liang, X. Liu, J. Yang, and J. Wei. 2019. Nrf2/Keap1/ARE Signaling mediated an antioxidative protection of human placental mesenchymal stem cells of fetal origin in alveolar epithelial cells [J]. Oxidative Medicine and Cellular Longevity 2019: 2654910.
Bachofen, M., and E.R. Weibel. 1977. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia [J]. The American Review of Respiratory Disease 116 (4): 589–615.
Asti, C., V. Ruggieri, S. Porzio, R. Chiusaroli, G. Melillo, and G.F. Caselli. 2000. Lipopolysaccharide-induced lung injury in mice. I. Concomitant evaluation of inflammatory cells and haemorrhagic lung damage. Pulmonary Pharmacology & Therapeutics 13 (2): 61–69.
Matute-Bello, G., C.W. Frevert, and T.R. Martin. 2008. Animal models of acute lung injury. American Journal of Physiology. Lung Cellular and Molecular Physiology 295 (3): L379–L399.
Oita, M., H. Miyoshi, K. Ono, A. Nakamura, K.Y. Cho, H. Nomoto, K. Yamamoto, K. Omori, N. Manda, Y. Kurihara, S. Aoki, and T. Atsumi. 2018. Satisfaction and efficacy of switching from daily dipeptidyl peptidase-4 inhibitors to weekly trelagliptin in patients with type 2 diabetes-Randomized controlled study [J]. Endocrine Journal 65 (2): 141–150.
Nishimura, R., T. Osonoi, Y. Koike, and K. Miyata. 2019. Shimasaki Y. A randomized pilot study of the effect of Trelagliptin and alogliptin on glycemic variability in patients with type 2 diabetes [J]. Advances in Therapy 36 (11): 3096–3109.
Aroor, A.R., J. Habibi, H.K. Kandikattu, M. Garro-Kacher, B. Barron, D. Chen, M.R. Hayden, A. Whaley-Connell, S.B. Bender, T. Klein, J. Padilla, J.R. Sowers, B. Chandrasekar, and V.G. DeMarco. 2017. Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice [J]. Cardiovascular Diabetology 16 (1): 61.
Nakagami, H., Z. Pang, T. Shimosato, T. Moritani, H. Kurinami, H. Koriyama, A. Tenma, M. Shimamura, and R. Morishita. 2014. The dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial dysfunction and insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome [J]. Hypertension research : official journal of the Japanese Society of Hypertension 37 (7): 629–635.
Matthay, M.A., and G.A. Zimmerman. 2005. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. American Journal of Respiratory Cell and Molecular Biology 33: 319–327.
Wang, G., B. Wu, L. Zhang, X. Jin, K. Wang, W. Xu, B. Zhang, and H. Wang. 2021. The protective effects of trelagliptin on high-fat diet-induced nonalcoholic fatty liver disease in mice. Journal of Biochemical and Molecular Toxicology: e22696.
Paglia, D.E., and W.N. Valentine. 1967. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase [J]. The Journal of Laboratory and Clinical Medicine 70 (1): 158–169.
Dong, L., and L. Li. 2019. Lats2-underexpressing bone marrow-derived mesenchymal stem cells ameliorate LPS-induced acute lung injury in mice [J]. Mediators of Inflammation 2019: 4851431.
Kluge, S., T. Muller, and M. Pfeifer. 2011. [Current approaches to the treatment of severe hypoxic respiratory insufficiency (acute lung injury; acute respiratory distress syndrome)] [J]. Deutsche Medizinische Wochenschrift 136 (5): 186–189.
Hager, D.N. 2015. Recent Advances in the Management of the Acute Respiratory Distress Syndrome [J]. Clinics in Chest Medicine 36 (3): 481–496.
Bender, S.P., E.P. Anderson, R.I. Hieronimus, and A. Bensimhon. One-Lung Ventilation and Acute Lung Injury [J]. International Anesthesiology Clinics 56 (1): 88–106.
Triantafyllou, G.A., P.J. Tiberio, R.H. Zou, P.E. Lamberty, M.J. Lynch, J.W. Kreit, M.T. Gladwin, A. Morris, and J. Chiarchiaro. 2019. Vaping-associated Acute Lung Injury: A Case Series [J]. American Journal of Respiratory and Critical Care Medicine 200 (11): 1430–1431.
Dias-Freitas, F., C. Metelo-Coimbra, and R. Roncon-Albuquerque Jr. 2016. Molecular mechanisms underlying hyperoxia acute lung injury [J]. Respiratory Medicine 119: 23–28.
Mould, K.J., and W.J. Janssen. 2018. Recombinant IFN-beta for postseptic acute lung injury-what’s the mechanism? [J]. American Journal of Respiratory Cell and Molecular Biology 59 (1): 1–2.
Lei, J., Y. Wei, P. Song, Y. Li, T. Zhang, Q. Feng, and G. Xu. 2018. Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress [J]. European Journal of Pharmacology 818: 110–114.
Zhu, T., X. Guan, W. Zhang, and D. Wang. 2012. [Dehydroandrographolide succinate inhibits oxidative stress in mice with lipopolysaccharide-induced acute lung injury by inactivating iNOS] [J]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 32 (9): 1238–1241.
Zhang, H.X., S.J. Liu, X.L. Tang, G.L. Duan, X. Ni, X.Y. Zhu, Y.J. Liu, and C.N. Wang. 2016. H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation [J]. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 40 (6): 1603–1612.
Suzuki, T., Y. Tada, S. Gadson, R. Nishimura, I. Shimomura, S. Karasawa, K. Tatsumi, and J. West. 2017. Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition. Respiratory Research 18 (1): 177.
Kawasaki, T., W. Chen, Y.M. Htwe, K. Tatsumi, and S.M. Dudek. 2018. DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice. American Journal of Physiology. Lung Cellular and Molecular Physiology 315 (5): L834–L845.
Guo, K., and F. Jin. 2019. Dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin alleviates lipopolysaccharide-induced acute lung injury via regulating the Nrf-2/HO-1 and NF-κB pathways. Journal of Investigative Surgery: 1–8. https://doi.org/10.1080/08941939.2019.1680777.
Vettorazzi, S., C. Bode, L. Dejager, L. Frappart, E. Shelest, C. Klaßen, A. Tasdogan, H.M. Reichardt, C. Libert, M. Schneider, F. Weih, N. Henriette Uhlenhaut, J.P. David, M. Gräler, A. Kleiman, and J.P. Tuckermann. 2015. Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. Nature Communications 6: 7796.
Hwang, J.S., K.H. Kim, J. Park, S.M. Kim, H. Cho, Y. Lee, and I.O. Han. 2019. Glucosamine improves survival in a mouse model of sepsis and attenuates sepsis-induced lung injury and inflammation. The Journal of Biological Chemistry 294 (2): 608–622.
Bosma, K.J., R. Taneja, and J.F. Lewis. 2010. Pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: current and experimental approaches. Drugs. 70 (10): 1255–1282.
Jiang, K., T. Zhang, N. Yin, X. Ma, G. Zhao, H. Wu, C. Qiu, and G. Deng. 2017. Geraniol alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis. Oncotarget. 8 (41): 71038–71053.
Tighe, R.M., A. Birukova, M.J. Yaeger, S.W. Reece, and K.M. Gowdy. 2018. Euthanasia- and lavage-mediated effects on bronchoalveolar measures of lung injury and inflammation. American Journal of Respiratory Cell and Molecular Biology 59 (2): 257–266.
Tang, S.E., S.Y. Wu, S.J. Chu, Y.S. Tzeng, C.K. Peng, C.C. Lan, W.C. Perng, C.P. Wu, and K.L. Huang. 2019. Pre-treatment with ten-minute carbon dioxide inhalation prevents lipopolysaccharide-induced lung injury in mice via down-regulation of toll-like receptor 4 expression. International Journal of Molecular Sciences 20 (24): 6293.
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This work was supported by the 2018 Guiding Project of Hengyang Science and Technology Bureau (S2018F9031021271).
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Zhou, J., Peng, Z. & Wang, J. Trelagliptin Alleviates Lipopolysaccharide (LPS)-Induced Inflammation and Oxidative Stress in Acute Lung Injury Mice. Inflammation 44, 1507–1517 (2021). https://doi.org/10.1007/s10753-021-01435-w
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DOI: https://doi.org/10.1007/s10753-021-01435-w