Advertisement

Glycyrrhizin Treatment Is Associated with Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Expression

Published:November 02, 2010DOI:https://doi.org/10.1016/j.jss.2010.10.004
      Glycyrrhizin (GL), a major active constituent of licorice root, has been attributed numerous pharmacologic effects, including anti-inflammatory, anti-viral, anti-tumor, and hepatoprotective activities. In this study, we investigated the anti-inflammatory effect of GL on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in Balb/c mice by intratracheal instillation of LPS (1 mg/kg). Before 1 h of LPS administration, the mice received intraperitoneal injection of GL at varied doses (10, 25, and 50 mg/kg). The severity of pulmonary injury was evaluated 12 h after LPS administration. GL pretreatment led to significant attenuation of LPS induced evident lung histopathologic changes, alveolar hemorrhage, and neutrophil infiltration with evidence of reduced myeloperoxidase (MPO) activity. The lung wet/dry weight ratios, as an index of lung edema, were markedly reduced by GL pretreatment. The concentrations of pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α were elevated in bronchoalveolar lavage fluid (BALF) after LPS administration, which were significantly inhibited by GL pretreatment. GL pretreatment also reduced the concentrations of nitric oxide (NO) in lung tissues. Furthermore, the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was suppressed by GL pretreatment. In conclusion, GL potently protected against LPS-induced ALI, and the protective effects of GL may attribute partly to the suppression of COX-2 and iNOS expression.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Surgical Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ashbaugh D.G.
        • Bigelow D.B.
        • Petty T.L.
        • et al.
        Acute respiratory distress in adults.
        Lancet. 1967; 2: 319
        • Ware L.B.
        • Matthay M.A.
        The acute respiratory distress syndrome.
        N Engl J Med. 2000; 342: 1334
        • Rubenfeld G.D.
        • Caldwell E.
        • Peabody E.
        • et al.
        Incidence and outcomes of acute lung injury.
        N Engl J Med. 2005; 353: 1685
        • Wheeler A.P.
        • Bernard G.R.
        Acute lung injury and the acute respiratory distress syndrome: A clinical review.
        Lancet. 2007; 369: 1553
        • Ejima K.
        • Layne M.D.
        • Carvajal I.M.
        • et al.
        Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death.
        FASEB J. 2003; 17: 1325
        • Funk C.D.
        Prostaglandin and leukotrienes: Advances in eicosanoid biology.
        Science. 2001; 294: 1871
        • Kim S.O.
        • Kundu J.K.
        • Shin Y.K.
        • et al.
        [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF- κB in phorbol ester-stimulated mouse skin.
        Oncogene. 2005; 24: 2558
        • Iadecola C.
        • Niwa K.
        • Nogawa S.
        • et al.
        Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice.
        Proc Natl Acad Sci USA. 2001; 98: 1294
        • Peng X.
        • Abdulnour R.E.
        • Sammani S.
        • et al.
        Inducible nitric oxide synthase contributes to ventilator-induced lung injury.
        Am J Respir Crit Care Med. 2005; 172: 470
        • Kristof A.S.
        • Goldberg P.
        • Laubach V.
        • et al.
        Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury.
        Am J Respir Crit Care Med. 1998; 158: 1883
        • Genovese T.
        • Cuzzocrea S.
        • Di Paola R.
        • et al.
        Inhibition or knock out of inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury.
        Respir Res. 2005; 6: 58
        • Matsui S.
        • Matsumoto H.
        • Sonoda Y.
        • et al.
        Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line.
        Int Immunopharmacol. 2004; 4: 1633
        • Park H.Y.
        • Park S.H.
        • Yoon H.K.
        • et al.
        Anti-allergic activity of 18 beta-glycyrrhetinic acid-3-O-beta-D-glucuronide.
        Arch Pharm Res. 2004; 27: 57
        • Sato H.
        • Goto W.
        • Yamamura J.
        • et al.
        Therapeutic basis of glycyrrhizin on chronic hepatitis B.
        Antiviral Res. 1996; 30: 171
        • Yoshida T.
        • Abe K.
        • Ikeda T.
        • et al.
        Inhibitory effect of glycyrrhizin on lipopolysaccharide and d-galactosamine-induced mouse liver injury.
        Eur J Pharmacol. 2007; 576: 136
        • Tsuruoka N.
        • Abe K.
        • Wake K.
        • et al.
        Hepatic protection by glycyrrhizin and inhibition of iNOS expression in concanavalin A-induced liver injury in mice.
        Inflamm Res. 2009; 58: 593
        • Fenton M.J.
        • Golenbock D.T.
        LPS-binding proteins and receptors.
        J Leukoc Biol. 1998; 64: 25
        • Goodman R.B.
        • Pugin J.
        • Lee J.S.
        • et al.
        Cytokine-mediated inflammation in acute lung injury.
        Cytokine Growth Factor Rev. 2003; 14: 523
        • Lee C.H.
        • Park S.W.
        • Kim Y.S.
        • et al.
        Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice.
        Biol Pharm Bull. 2007; 30: 1898
        • Tang B.
        • Qiao H.
        • Meng F.
        • et al.
        Glycyrrhizin attenuates endotoxin- induced acute liver injury after partial hepatectomy in rats.
        Braz J Med Biol Res. 2007; 40: 1637
        • Zhao X.
        • Zmijewski J.W.
        • Lorne E.
        • et al.
        Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury.
        Am J Physiol Lung Cell Mol Physiol. 2008; 295: 497
        • Bradley P.P.
        • Priebat D.A.
        • Christensen R.D.
        • et al.
        Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker.
        J Invest Dermatol. 1982; 78: 206
        • Li X.Y.
        • Donaldson K.
        • Macnee W.
        Lipopolysaccharide-induced alveolar epithelial permeability: The role of nitric oxide.
        Am J Respir Crit Care Med. 1998; 157: 1027
        • Sittipunt C.
        • Steinberg K.P.
        • Ruzinski J.T.
        • et al.
        Nitric oxide and nitrotyrosine in the lungs of patients with acute respiratory distress syndrome.
        Am J Respir Crit Care Med. 2001; 163: 503
        • Wang L.F.
        • Patel M.
        • Razavi H.M.
        • et al.
        Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis.
        Am J Respir Crit Care Med. 2002; 165: 1634
        • Ermert M.
        • Ruppert C.
        • Gunther A.
        • et al.
        Cell-specific nitric oxide synthase-isoenzyme expression and regulation in response to endotoxin in intact rat lungs.
        Lab Invest. 2002; 82: 425
        • Hempel S.L.
        • Monick M.M.
        • Hunninghake G.W.
        Lipopolysaccharide induces prostaglandin H synthase-2 protein and mRNA in human alveolar macrophages and blood monocytes.
        J Clin Invest. 1994; 93: 391
        • Lee S.H.
        • Soyoola E.
        • Chanmugam P.
        • et al.
        Selective expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide.
        J Biol Chem. 1992; 267: 25934
        • Mitchell J.A.
        • Belvisi M.G.
        • Akarasereenont P.
        • et al.
        Induction of cyclooxygenase-2 by cytokines in human pulmonary epithelial cells: Regulation by dexamethasone.
        Br J Pharmacol. 1994; 113: 1008
        • Ermert L.
        • Ermert M.
        • Merkle M.
        • et al.
        Rat pulmonary cyclooxygenase-2 expression in response to endotoxin challenge: Differential regulation in the various types of cells in the lung.
        Am J Pathol. 2000; 156: 1275
        • Ethridge R.T.
        • Chung D.H.
        • Slogoff M.
        • et al.
        Cyclooxygenase-2 gene disruption attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury.
        Gastroenterology. 2002; 123: 1311
        • Gust R.
        • Kozlowski J.K.
        • Stephenson A.H.
        Role of cyclooxygenase-2 in oleic acid-induced acute lung injury.
        Am J Respir Crit Care Med. 1999; 160: 1165
        • Xie Q.W.
        • Kashiwabara Y.
        • Nathan C.
        Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase.
        J Biol Chem. 1994; 269: 4705
        • von Knethen A.
        • Callsen D.
        • Brüne B.
        Superoxide attenuates macrophage apoptosis by NF-κB and AP-1 activation that promotes cyclooxygenase-2 expression.
        J Immunol. 1999; 163: 2858