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Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function


Glucagon-like peptide-1 (GLP-1), which is well known for regulating glucose homeostasis, exhibits multiple actions in cardiovascular disorders and renal injury. However, little is known about the effect of GLP-1 receptor (GLP-1R) activation on acute lung injury (ALI). In this study, we investigated the effect of GLP-1R on ALI and the potential underlying mechanisms with the selective agonist liraglutide. Our results show that GLP-1 levels decreased in serum, though they increased in bronchoalveolar lavage fluid (BALF) and lung tissue in a mouse model of lipopolysaccharide (LPS)-induced ALI. Liraglutide prevented LPS-induced polymorphonuclear neutrophil (PMN) extravasation, lung injury, and alveolar-capillary barrier dysfunction. In cultured human pulmonary microvascular endothelial cells (HPMECs), liraglutide protected against LPS-induced endothelial barrier injury by restoring intercellular tight junctions and adherens junctions. Moreover, liraglutide prevented PMN–endothelial adhesion by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and thereafter suppressed PMN transendothelial migration. Furthermore, liraglutide suppressed LPS-induced activation of Rho/NF-κB signaling in HPMECs. In conclusion, our results show that GLP-1R activation protects mice from LPS-induced ALI by maintaining functional endothelial barrier and inhibiting PMN extravasation. These results also suggest that GLP-1R may be a potential therapeutic target for the treatment of ALI.

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  1. 1.

    Fanelli V, Ranieri VM. Mechanisms and clinical consequences of acute lung injury. Ann Am Thorac Soc. 2015;12(Suppl. 1):S3–8.

  2. 2.

    Petty TL, Ashbaugh DG. The adult respiratory distress syndrome. Clinical features, factors influencing prognosis and principles of management. Chest. 1971;60:233–9.

  3. 3.

    Muller-Redetzky HC, Suttorp N, Witzenrath M. Dynamics of pulmonary endothelial barrier function in acute inflammation: mechanisms and therapeutic perspectives. Cell Tissue Res. 2014;355:657–73.

  4. 4.

    Herold S, Gabrielli NM, Vadasz I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2013;305:L665–81.

  5. 5.

    Oliveira SDS, Castellon M, Chen J, et al. Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-beta-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 2017;312:L760–71.

  6. 6.

    Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27:740–56.

  7. 7.

    Wang C, Li L, Liu S, et al. GLP-1 receptor agonist ameliorates obesity-induced chronic kidney injury via restoring renal metabolism homeostasis. PLoS ONE. 2018;13:e0193473.

  8. 8.

    Chen P, Shi X, Xu X, et al. Liraglutide ameliorates early renal injury by the activation of renal FoxO1 in a type 2 diabetic kidney disease rat model. Diabetes Res Clin Pract. 2018;137:173–82.

  9. 9.

    Xie Z, Enkhjargal B, Wu L, et al. Exendin-4 attenuates neuronal death via GLP-1R/PI3K/Akt pathway in early brain injury after subarachnoid hemorrhage in rats. Neuropharmacology. 2018;128:142–51.

  10. 10.

    Zhang Y, Ling Y, Yang L, et al. Liraglutide relieves myocardial damage by promoting autophagy via AMPK-mTOR signaling pathway in zucker diabetic fatty rat. Mol Cell Endocrinol. 2017;448:98–107.

  11. 11.

    Kim S, Jeong J, Jung HS, et al. Anti-inflammatory effect of glucagon like peptide-1 receptor agonist, exendin-4, through modulation of IB1/JIP1 expression and JNK signaling in stroke. Exp Neurobiol. 2017;26:227–39.

  12. 12.

    Hu SY, Zhang Y, Zhu PJ, et al. Liraglutide directly protects cardiomyocytes against reperfusion injury possibly via modulation of intracellular calcium homeostasis. J Geriatr Cardiol. 2017;14:57–66.

  13. 13.

    Abdelsameea AA, Abbas NA, Abdel Raouf SM. Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers. Naunyn Schmiede Arch Pharmacol. 2017;390:311–9.

  14. 14.

    Garczorz W, Gallego-Colon E, Kosowska A, et al. Exenatide exhibits anti-inflammatory properties and modulates endothelial response to tumor necrosis factor alpha-mediated activation. Cardiovasc Ther. 2018;36:12317

  15. 15.

    Li Q, Lin Y, Wang S, et al. GLP-1 inhibits high-glucose-induced oxidative injury of vascular endothelial cells. Sci Rep. 2017;7:8008.

  16. 16.

    Zhang Y, Zhou H, Wu W, et al. Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2+)-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways. Free Radic Biol Med. 2016;95:278–92.

  17. 17.

    Fukuda S, Nakagawa S, Tatsumi R, et al. Glucagon-like peptide-1 strengthens the barrier integrity in primary cultures of rat brain endothelial cells under basal and hyperglycemia conditions. J Mol Neurosci. 2016;59:211–9.

  18. 18.

    Mitchell PD, Salter BM, Oliveria JP, et al. Glucagon-like peptide-1 receptor expression on human eosinophils and its regulation of eosinophil activation. Clin Exp Allergy. 2017;47:331–8.

  19. 19.

    Bruen R, Curley S, Kajani S, et al. Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis. Cardiovasc Diabetol. 2017;16:143.

  20. 20.

    Dokken BB, La Bonte LR, Davis-Gorman G, et al. Glucagon-like peptide-1 (GLP-1), immediately prior to reperfusion, decreases neutrophil activation and reduces myocardial infarct size in rodents. Horm Metab Res. 2011;43:300–5.

  21. 21.

    Matute-Bello G, Downey G, Moore BB, et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol. 2011;44:725–38.

  22. 22.

    Moitra J, Sammani S, Garcia JG. Re-evaluation of Evans Blue dye as a marker of albumin clearance in murine models of acute lung injury. Transl Res. 2007;150:253–65.

  23. 23.

    Wang JJ, Zuo XR, Xu J, et al. Evaluation and treatment of endoplasmic reticulum (ER) stress in right ventricular dysfunction during monocrotaline-induced rat pulmonary arterial hypertension. Cardiovasc Drugs Ther. 2016;30:587–98.

  24. 24.

    Wang J, Xu J, Zhao X, et al. Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2. Exp Cell Res. 2018;365:97–105.

  25. 25.

    Xu J, Wang J, He M, et al. Dipeptidyl peptidase IV (DPP-4) inhibition alleviates pulmonary arterial remodeling in experimental pulmonary hypertension. Lab Invest. 2018;98:1333–46.

  26. 26.

    Duluc L, Wojciak-Stothard B. Rho GTPases in the regulation of pulmonary vascular barrier function. Cell Tissue Res. 2014;355:675–85.

  27. 27.

    Cernuda-Morollon E, Ridley AJ. Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ Res. 2006;98:757–67.

  28. 28.

    Fan Y, Liu K, Wang Q, et al. Exendin-4 alleviates retinal vascular leakage by protecting the blood-retinal barrier and reducing retinal vascular permeability in diabetic Goto-Kakizaki rats. Exp Eye Res. 2014;127:104–16.

  29. 29.

    Goncalves A, Lin CM, Muthusamy A, et al. Protective effect of a GLP-1 analog on ischemia-reperfusion induced blood-retinal barrier breakdown and inflammation. Invest Ophthalmol Vis Sci. 2016;57:2584–92.

  30. 30.

    Nozu T, Miyagishi S, Kumei S, et al. Glucagon-like peptide-1 analog, liraglutide, improves visceral sensation and gut permeability in rats. J Gastroenterol Hepatol. 2018;33:232–9.

  31. 31.

    Kreuger J, Phillipson M. Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis. Nat Rev Drug Discov. 2016;15:125–42.

  32. 32.

    Krasner NM, Ido Y, Ruderman NB, et al. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS ONE. 2014;9:e97554.

  33. 33.

    Kosowska A, Gallego-Colon E, Garczorz W, et al. Exenatide modulates tumor-endothelial cell interactions in human ovarian cancer cells. Endocr Connect. 2017;6:856–65.

  34. 34.

    Gumuslu E, Cine N, Ertan Gokbayrak M, et al. Exenatide alters gene expression of neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the hippocampus of type 2 diabetic model mice. Med Sci Monit. 2016;22:2664–9.

  35. 35.

    Wang D, Luo P, Wang Y, et al. Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes. 2013;62:1697–708.

  36. 36.

    Kong X, Yan D, Sun J, et al. Glucagon-like peptide 1 stimulates insulin secretion via inhibiting RhoA/ROCK signaling and disassembling glucotoxicity-induced stress fibers. Endocrinology. 2014;155:4676–85.

  37. 37.

    Tang ST, Zhang Q, Tang HQ, et al. Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor kappaB signaling pathways. Endocrine. 2016;53:107–16.

  38. 38.

    Cheang JY, Moyle PM. Glucagon-like peptide-1 (GLP-1)-based therapeutics: current status and future opportunities beyond type 2 diabetes. ChemMedChem. 2018;13:662–71.

  39. 39.

    Xu J, Wang J, Cheng Y, et al. Glucagon-like peptide-1 mediates the protective effect of the dipeptidyl peptidase iv inhibitor on renal fibrosis via reducing the phenotypic conversion of renal microvascular cells in monocrotaline-treated rats. Biomed Res Int. 2018;2018:1864107.

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This study was supported by the National Natural Science Foundation of China (No. 81273571, No. 81870054), the Jiangsu Clinical Research Center for Respiratory Diseases Project under Grant BL2012012, the Jiangsu Province Scientific Research Innovation Project of University graduate students (JX22013361), and by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (JX10231802).

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Correspondence to Weiping Xie or Hui Kong.

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