Geniposide, an Iridoid Glucoside Derived from Gardenia jasminoides, Protects against Lipopolysaccharide-Induced Acute Lung Injury in Mice

Abstract

Geniposide, a main iridoid glucoside component of gardenia fruit, has been shown to possess anti-inflammatory activity. However, its potential use for acute lung injury (ALI) has not yet been studied. The aim of this study was to evaluate the anti-inflammatory properties of geniposide using a mouse ALI model. ALI was induced by intranasal injection of lipopolysaccharide (LPS). Pretreatment of mice with geniposide (20, 40, or 80 mg/kg) resulted in a marked reduction in inflammatory cells and total protein concentration in the bronchoalveolar lavage fluid (BALF) of mice. Levels of inflammatory mediators, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10), were significantly altered after treatment with geniposide. Histological studies using hematoxylin and eosin (H&E) staining demonstrate that geniposide substantially inhibited LPS-induced alveolar wall changes, alveolar haemorrhage, and neutrophil infiltration in lung tissue, with evidence of reduced myeloperoxidase (MPO) activity. In addition, we investigated potential signal transduction mechanisms that could be implicated in geniposide activity. Our results suggest that geniposide may provide protective effects against LPS-induced ALI by mitigating inflammatory responses and that the compound's mechanism of action may involve blocking nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPK) signalling pathway activation.

geniposide - lipopolysaccharide - acute lung injury - cytokine - nuclear factor-kappaB - mitogen-activated protein kinases - Gardenia jasminoides - Rubiaceae

References

• 1 Prudhomme J B, Ware L B. Acute lung injury and acute respiratory distress syndrome: mechanisms and potential new therapies.  Drug Discov Today. 2004;  1 123-128
• 2 Lee W L, Downey G P. Neutrophil activation and acute lung injury.  Curr Opin Crit Care. 2001;  7 1-7
• 3 Abraham E. Neutrophils and acute lung injury.  Crit Care Med. 2003;  31 S195-S199
• 4 Cribbs S K, Matthay M A, Martin G S. Stem cells in sepsis and acute lung injury.  Crit Care Med. 2010;  38 2379-2385
• 5 Mayeux P R. Pathobiology of lipopolysaccharide.  J Toxicol Environ Health. 1997;  51 415-435
• 6 Martin M A, Silverman H J. Gram-negative sepsis and the adult respiratory distress syndrome.  Clin Infect Dis. 1992;  14 1213-1228
• 7 Diaz J V, Brower R, Calfee C S, Matthay M A. Therapeutic strategies for severe acute lung injury.  Crit Care Med. 2010;  38 1644-1650
• 8 Matthay M A, Goolaerts A, Howard J P, Lee J W. Mesenchymal stem cells for acute lung injury: preclinical evidence.  Crit Care Med. 2010;  38 S569-S573
• 9 Yang W, Qiang D, Zhang M, Ma L, Zhang Y, Qing C, Xu Y, Zhen C, Liu J, Chen Y H. Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models.  Int Immunopharmacol. 2011;  11 683-692
• 10 Tseng T H, Chu C Y, Huang J M, Shiow S J, Wang C J. Crocetin protects against damage in rat primary hepatocytes.  Cancer Lett. 1995;  97 61-67
• 11 Lee J H, Lee D U, Jeong C S. Gardenia jasminoides Ellis ethanol extract and its constituents reduce the risks of gastritis and reverse gastric lesions in rats.  Food Chem Toxicol. 2009;  47 1127-1131
• 12 Jung W S, Chae Y S, Kim D Y, Seo S W, Park H J, Bae G S, Kim T H, Oh H J, Yun K J, Park R K, Kim J S, Kim E C, Hwang S Y, Park S J, Song H J. Gardenia jasminoides protects against cerulein-induced acute pancreatitis.  World J Gastroenterol. 2008;  14 6188-6194
• 13 Jagadeeswaran R, Thirunavukkarasu C, Gunasekaran P, Ramamurty N, Sakthisekaran D. In vitro studies on the selective cytotoxic effect of crocetin and quercetin.  Fitoterapia. 2000;  71 395-399
• 14 Koo H J, Song Y S, Kim H J, Lee Y H, Hong S M, Kim S J, Kim B C, Jin C, Lim C J, Park E H. Antiinflammatory effects of genipin, an active principle of Gardenia.  Eur J Pharmacol. 2004;  495 201-208
• 15 Chen Q C, Zhang W Y, Youn U, Kim H, Lee I, Jung H J, Na M, Min B S, Bae K. Iridoid glycosides from Gardeniae fructus for treatment of ankle sprain.  Phytochemistry. 2009;  70 779-784
• 16 Liaw J, Chao Y C. Effect of in vitro and in vivo aerosolized treatment with geniposide on tracheal permeability in ovalbumin-induced guinea pigs.  Eur J Pharmacol. 2001;  433 115-121
• 17 Koo H J, Lim K H, Jung H J, Park E H. Anti-inflammatory evaluation of gardenia extract, geniposide and genipin.  J Ethnopharmacol. 2006;  103 496-500
• 18 Liu J, Yin F, Zheng X, Jing J, Hu Y. Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway.  Neurochem Int. 2007;  51 361-369
• 19 Wang G F, Wu S Y, Xu W, Jin H, Zhu Z G, Li Z H, Tian Y X, Zhang J J, Rao J J, Wu S G. Geniposide inhibits high glucose-induced cell adhesion through the NF-kappaB signaling pathway in human umbilical vein endothelial cells.  Acta Pharmacol Sin. 2010;  31 953-962
• 20 Ma T, Huang C, Zong G, Zha D, Meng X, Li J, Tang W. Hepatoprotective effects of geniposide in a rat model of nonalcoholic steatohepatitis.  J Pharm Pharmacol. 2011;  63 587-593
• 21 Zheng X, Yang D, Liu X, Wang N, Li B, Cao H, Lu Y, Wei G, Zhou H, Zheng J. Identification of a new anti-LPS agent, geniposide, from Gardenia jasminoides Ellis, and its ability of direct binding and neutralization of lipopolysaccharide in vitro and in vivo.  Int Immunopharmacol. 2010;  10 1209-1219
• 22 Wang X Q, Zhou X, Zhou Y, Rong L, Gao L, Xu W. Low-dose dexamethasone alleviates lipopolysaccharide-induced acute lung injury in rats and upregulates pulmonary glucocorticoid receptors.  Respirology. 2008;  13 772-780
• 23 Szarka R J, Wang N, Gordon L, Nation P N, Smith R H. A murine model of pulmonary damage induced by lipopolysaccharide via intranasal instillation.  J Immunol Methods. 1997;  202 49-57
• 24 Liu Y, Wu H, Nie Y C, Chen J L, Su W W, Li P B. Naringin attenuates acute lung injury in LPS-treated mice by inhibiting NF-κB pathway.  Int Immunopharmacol. 2011;  10 1606-1612
• 25 Wu Y, Singer M, Thouron F, Alaoui-El-Azher M, Touqui L. Effect of surfactant on pulmonary expression of type IIA PLA(2) in an animal model of acute lung injury.  Am J Physiol Lung Cell Mol Physiol. 2002;  282 L743-L750
• 26 Lin Q, Wang G F, Tang X Y, Zou S L. Effects of dexamethasone on acute lung injury in rats induced by lipopolysacharide.  Beijing Da Xue Xue Bao. 2006;  38 393-396
• 27 Kunkel S L, Standiford T, Kasahara K, Strieter R M. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung.  Exp Lung Res. 1991;  17 17-23
• 28 Goodman R B, Pugin J, Lee J S, Matthay M A. Cytokine-mediated inflammation in acute lung injury.  Cytokine Growth Factor Rev. 2003;  14 523-535
• 29 Giebelen I A, van Westerloo D J, LaRosa G J, de Vos A F, van der Poll T. Local stimulation of alpha7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung.  Shock. 2007;  28 700-703
• 30 Ewaschuk J, Endersby R, Thiel D, Diaz H, Backer J, Ma M, Churchill T, Madsen K. Probiotic bacteria prevent hepatic damage and maintain colonic barrier function in a mouse model of sepsis.  Hepatology. 2007;  46 841-850
• 31 Xu X L, Xie Q M, Shen Y H, Jiang J J, Chen Y Y, Yao H Y, Zhou J Y. Mannose prevents lipopolysaccharide-induced acute lung injury in rats.  Inflamm Res. 2008;  57 104-110
• 32 Lim J Y, Won T J, Hwang B Y, Kim H R, Hwang K W, Sul D, Park S Y. The new diterpene isodojaponin D inhibited LPS-induced microglial activation through NF-kappaB and MAPK signaling pathways.  Eur J Pharmacol. 2010;  642 10-18

1 Yang Xiaofeng and Cai Qinren contributed equally to this work.