Abstracts
Purpose
Sepsis has a high mortality rate despite the recent advances in intensive care medicine and antibiotics. Honokiol, a low molecular weight natural product, is known to possess anti-inflammatory activity. Here, we investigate whether honokiol can ameliorate acute lung injury and lethal response in murine models of sepsis.
Methods
Mice were intraperitoneally given vehicle or honokiol 30Â min after the induction of sepsis by cecal ligation and puncture (CLP) and endotoxemia by administration of E. coli lipopolysaccharide (LPS).
Results
The productions of serum tumor necrosis factor-α (TNF-α), nitric oxide (NO), and high mobility group box 1 (HMGB 1) were increased in mice during sepsis, which could be reversed by honokiol. Honokiol could also effectively reduce the increased blood lipid peroxidation and nitrotyrosine in septic mice. Honokiol significantly reversed the inductions of inducible NO synthase and nuclear factor-κB (NF-κB) activation in the lungs of mice during sepsis. Honokiol also effectively rescued the lung edema, lung pathological changes, and lethality in septic mice.
Conclusions
These findings suggest that honokiol is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the potential use of honokiol as a therapeutic agent for the conditions associated with septic shock.
Similar content being viewed by others
References
Shimaoka M, Park EJ (2008) Advances in understanding sepsis. Eur J Anaesthesiol 42(Suppl):146–153
Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251
Abraham E, Nick JA, Azam T, Kim SH, Mira JP, Svetkauskaite D, He Q, Zamora M, Murphy J, Park JS, Overdier K, Dinarello CA (2006) Peripheral blood neutrophil activation patterns are associated with pulmonary inflammatory responses to lipopolysaccharide in humans. J Immunol 176:7753–7760
Abraham E, Carmody A, Shenkar R, Arcaroli J (2000) Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 279:L1137–L1145
Silva E, Arcaroli J, He Q, Svetkauskaite D, Coldren C, Nick JA, Poch K, Park JS, Banerjee A, Abraham E (2007) HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis-induced acute lung injury. Intensive Care Med 33:1829–1839
Asehnoune K, Strassheim D, Mitra S, Kim JY, Abraham E (2004) Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-κB. J Immunol 172:2522–2529
Aderem A, Ulevitch RJ (2000) Toll-like receptors in the induction of the innate immune response. Nature 406:782–787
Liang Y, Zhou Y, Shen P (2004) NF-κB and its regulation on the immune system. Cell Mol Immunol 1:343–350
Palsson-McDermott EM, O’Neill LA (2004) Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 113:153–162
Wang H, Yang H, Czura CJ, Sama AE, Tracey KJ (2001) HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med 164:1768–1773
Rauvala H, Rouhiainen A (2007) RAGE as a receptor of HMGB1 (Amphoterin): roles in health and disease. Curr Mol Med 7:725–734
Kim JY, Park JS, Strassheim D, Douglas I, Diaz del Valle F, Asehnoune K, Mitra S, Kwak SH, Yamada S, Maruyama I, Ishizaka A, Abraham E (2005) HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol 288:L958–L965
Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, Kobayashi A, Maruyama I, Yamada S, Hasegawa N, Soejima J, Koh H, Ishizaka A (2004) Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med 170:1310–1316
Li W, Li J, Ashok M, Wu R, Chen D, Yang L, Yang H, Tracey KJ, Wang P, Sama AE, Wang H (2007) A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1. J Immunol 178:3856–3864
Fried L, Arbiser JL (2009) Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal 11:1139–1148
Son HJ, Lee HJ, Yun-Choi HS, Ryu JH (2000) Inhibitors of nitric oxide synthesis and TNF-α expression from Magnolia obovata in activated macrophages. Planta Med 66:469–471
Taira J, Ikemoto T, Mimura K, Hagi A, Murakami A, Makino K (1993) Effective inhibition of hydroxyl radicals by hydroxylated biphenyl compounds. Free Radic Res Commun 19(Suppl 1):S71–S77
Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 4:31–36
Chiang CK, Sheu ML, Hung KY, Wu KD, Liu SH (2006) Honokiol, a small molecular weight natural product, alleviates experimental mesangial proliferative glomerulonephritis. Kidney Int 70:682–689
Chiang J, Shen YC, Wang YH, Hou YC, Chen CC, Liao JF, Yu MC, Juan CW, Liou KT (2009) Honokiol protects rats against eccentric exercise-induced skeletal muscle damage by inhibiting NF-κB induced oxidative stress and inflammation. Eur J Pharmacol 610:119–127
Sheu ML, Chiang CK, Tsai KS, Ho FM, Weng TI, Wu HY, Liu SH (2008) Inhibition of NADPH oxidase-related oxidative stress-triggered signaling by honokiol suppresses high glucose-induced human endothelial cell apoptosis. Free Radic Biol Med 44:2043–2050
Torun AN, Kulaksizoglu S, Kulaksizoglu M, Pamuk BO, Isbilen E, Tutuncu NB (2009) Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clin Endocrinol (Oxf) 70:469–474
van der Vliet A, Eiserich JP, O’Neill CA, Halliwell B, Cross CE (1995) Tyrosine modification by reactive nitrogen species: a closer look. Arch Biochem Biophys 329:341–349
Matthay MA, Zimmerman GA, Esmon C, Bhattacharya J, Coller B, Doerschuk CM, Floros J, Gimbrone MA Jr, Hoffman E, Hubmayr RD, Leppert M, Matalon S, Munford R, Parsons P, Slutsky AS, Tracey KJ, Ward P, Gail DB, Harabin AL (2003) Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med 167:1027–1035
Kabir K, Gelinas JP, Chen M, Chen D, Zhang D, Luo X, Yang JH, Carter D, Rabinovici R (2002) Characterization of a murine model of endotoxin-induced acute lung injury. Shock 17:300–303
Remick DG, Newcomb DE, Bolgos GL, Call DR (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13:110–116
Mishra V (2007) Oxidative stress and role of antioxidant supplementation in critical illness. Clin Lab 53:199–209
Chandra A, Enkhbaatar P, Nakano Y, Traber LD, Traber DL (2006) Sepsis: emerging role of nitric oxide and selectins. Clinics (Sao Paulo) 61:71–76
Mehta S (2005) The effects of nitric oxide in acute lung injury. Vasc Pharmacol 43:390–403
Annane D, Bellissant E, Cavaillon JM (2005) Septic shock. Lancet 365:63–78
Okamoto I, Abe M, Shibata K, Shimizu N, Sakata N, Katsuragi T, Tanaka K (2000) Evaluating the role of inducible nitric oxide synthase using a novel and selective inducible nitric oxide synthase inhibitor in septic lung injury produced by cecal ligation and puncture. Am J Respir Crit Care Med 162:716–722
Strunk V, Hahnenkamp K, Schneuing M, Fischer LG, Rich GF (2001) Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation. Anesth Analg 92:681–687
Szabó C, Thiemermann C, Wu CC, Perretti M, Vane JR (1994) Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc Natl Acad Sci U S A 91:271–275
Doğru-Abbasoğlu S, Parildar-Karpuzoğlu H, Balkan J, Aykaç-Toker G, Uysal M (2007) Nitrotyrosine formation and heme oxygenase-1 expression in endotoxemic cirrhotic rats. Arch Med Res 38:28–33
Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, Choe KH, Strassheim D, Pitts TM, Tracey KJ, Abraham E (2003) Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol 284:C870–C879
Sheehan M, Wong HR, Hake PW, Zingarelli B (2003) Parthenolide improves systemic hemodynamics and decreases tissue leukosequestration in rats with polymicrobial sepsis. Crit Care Med 31:2263–2270
Ho KY, Tsai CC, Chen CP, Chen CP, Lin TC, Lin CC (2001) Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytother Res 15:139–141
Lee SY, Cho JY (2009) Inhibitory effects of honokiol on LPS and PMA-induced cellular responses of macrophages and monocytes. BMB Rep 42:574–579
Lee J, Jung E, Park J, Jung K, Lee S, Hong S, Park J, Park E, Kim J, Park S, Park D (2005) Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling. Planta Med 71:338–343
Chao LK, Liao PC, Ho CL, Wang EI, Chuang CC, Chiu HW, Hung LB, Hua KF (2010) Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-κB pathway to reduce LPS-induced TNF-α and NO expression. J Agric Food Chem 58:3472–3478
Acknowledgments
This study was supported by research grant from the National Science Council of Taiwan (NSC97-2320-B-002-020-MY3).
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Weng, T.I., Wu, H.Y., Kuo, C.W. et al. Honokiol rescues sepsis-associated acute lung injury and lethality via the inhibition of oxidative stress and inflammation. Intensive Care Med 37, 533–541 (2011). https://doi.org/10.1007/s00134-010-2104-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-010-2104-1