Journal of Anesthesia

, Volume 21, Issue 2, pp 164–170 | Cite as

RETRACTED ARTICLE: Nafamostat mesilate inhibits the expression of HMGB1 in lipopolysaccharide-induced acute lung injury

  • Satoshi Hagiwara
  • Hideo Iwasaka
  • Takayuki Noguchi
Original articles



High mobility group box 1 (HMGB1) protein has recently been shown to be an important late mediator of acute lung injury and a promising therapeutic target. Nafamostat mesilate (NM) is a broad-range synthetic protease inhibitor with some anti-inflammatory action. The purpose of this study was to evaluate the effect of NM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats.


Male Wistar rats were given either saline (LPS group) or NM (NM+LPS group) 30 min before the intravenous injection of a bolus of LPS (5 mg·kg−1). After the administration of LPS, injury to the lung and the expression of HMGB1, tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) were examined.


Histological examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the NM+LPS group compared to the LPS group. Furthermore, the LPS-induced increases in PAI-1 activity and in plasma TNF-α concentrations were also lower in the rats given both NM and LPS than in the rats given LPS alone.


The anticoagulatory activity of NM may have inhibited PAI-1, while its anti-inflammatory activity blockaded TNF-α, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. These findings indicate that NM can inhibit the lung injury induced by LPS in rats. NM is an excellent candidate for use in new therapeutic strategies to prevent or minimize lung injury.

Key words

LPS Lung injury Sepsis Acute respiratory distress syndrome Anticoagulant 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Martin, GS, Mannino, DM, Eaton, S, Moss, M 2003The epidemiology of sepsis in the United States from 1979 through 2000N Engl J Med34815461554CrossRefPubMedGoogle Scholar
  2. 2.
    Wyncoll, DL, Evans, TW 1999Acute respiratory distress syndromeLancet354497501CrossRefPubMedGoogle Scholar
  3. 3.
    Hoyert, DL, Anderson, RN 2001Age-adjusted death rates: trend data based on the year 2000 standard populationNatl Vital Stat Rep4916Google Scholar
  4. 4.
    Riedemann, NC, Guo, RF, Ward, PA 2003The enigma of sepsisJ Clin Invest15460467CrossRefGoogle Scholar
  5. 5.
    Wang, H, Yang, H, Czura, CJ, Sama, AE, Tracey, KJ 2001HMGB1 as a late mediator of lethal systemic inflammationAm J Respir Crit Care Med16417681773CrossRefPubMedGoogle Scholar
  6. 6.
    Bustin, M 1999Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteinsMol Cell Biol1952375246PubMedCentralPubMedGoogle Scholar
  7. 7.
    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 1999HMG-1 as a late mediator of endotoxin lethality in miceScience285248251CrossRefPubMedGoogle Scholar
  8. 8.
    Wang, H, Vishnubhakat, JM, Bloom, O, Zhang, M, Ombrellino, M, Sama, A, Tracey, KJ 1999Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytesSurgery126389392CrossRefPubMedGoogle Scholar
  9. 9.
    Andersson, U, Wang, H, Palmblad, K, Aveberger, AC, Bloom, O, Erlandsson-Harris, H, Janson, A, Kokkola, R, Zhang, M, Yang, H, Tracey, KJ 2000High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytesJ Exp Med192565570CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Fiuza, C, Bustin, M, Talwar, S, Tropea, M, Gerstenberger, E, Shelhamer, JH, Suffredini, AF 2003Inflammation-promoting activity of HMGB1 on human microvascular endothelial cellsBlood10126522660CrossRefPubMedGoogle Scholar
  11. 11.
    Abraham, E, Arcaroli, J, Carmody, A, Wang, H, Tracey, KJ 2000HMGB1 as a mediator of acute lung inflammationJ Immunol16529502954CrossRefPubMedGoogle Scholar
  12. 12.
    Keck, T, Friebe, V, Warshaw, AL, Antoniu, BA, Waneck, G, Benz, S, Hopt, UT, Fernandez-del-Castillo, C 2005Pancreatic proteases in serum induce leukocyte-endothelial adhesion and pancreatic microcirculatory failurePancreatology5241250CrossRefPubMedGoogle Scholar
  13. 13.
    Noguchi, S, Nakatsuka, M, Konishi, H, Kamada, Y, Chekir, C, Kudo, T 2003Nafamostat mesilate suppresses NF-kappaB activation and NO overproduction in LPS-treated macrophagesInt Immunopharmacol313351344CrossRefPubMedGoogle Scholar
  14. 14.
    Kirschfink, M 2001Targeting complement in therapyImmunol Rev180177189CrossRefPubMedGoogle Scholar
  15. 15.
    Uchiba, M, Okajima, K, Murakami, K, Okabe, H, Takatsuki, K 1997Effect of nafamostat mesilate on pulmonary vascular injury induced by lipopolysaccharide in ratsAm J Respir Crit Care Med155711718CrossRefPubMedGoogle Scholar
  16. 16.
    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 2004Contributions of high mobility group box protein in experimental and clinical acute lung injuryAm J Respir Crit Care Med17013101316CrossRefPubMedGoogle Scholar
  17. 17.
    Wang, H, Yang, H, Tracey, KJ 2004Extracellular role of HMGB1 in inflammation and sepsisJ Intern Med255320331CrossRefPubMedGoogle Scholar
  18. 18.
    Kokkola, R, Andersson, A, Mullins, G, Ostberg, T, Treutiger, CJ, Arnold, B, Nawroth, P, Andersson, U, Harris, RA, Harris, HE 2005RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophagesScand J Immunol6119CrossRefPubMedGoogle Scholar
  19. 19.
    Park, JS, Svetkauskaite, D, He, Q, Kim, JY, Strassheim, D, Ishizaka, A, Abraham, E 2004Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 proteinJ Biol Chem27973707377CrossRefPubMedGoogle Scholar
  20. 20.
    Kaplan, JE, Malik, AB 1987Thrombin-induced intravascular coagulation: role in vascular injurySemin Thromb Hemost13398415CrossRefPubMedGoogle Scholar
  21. 21.
    Hasegawa, N, Husari, AW, Hart, WT, Kandra, TG, Raffin, TA 1994Role of the coagulation system in ARDSChest105268277CrossRefPubMedGoogle Scholar
  22. 22.
    Okajima, K, Harada, N, Uchiba, M 2003Microthrombus formation enhances tumor necrosis factor-alpha production in the development of ischemia/reperfusion-induced liver injury in ratsJ Thromb Haemost113161317CrossRefPubMedGoogle Scholar
  23. 23.
    Aoyama, T, Ino, Y, Ozeki, M, Oda, M, Sato, T, Koshiyama, Y, Suzuki, S, Fujita, M 1984Pharmacological studies of FUT-175, nafamostat mesilate. I. Inhibition of protease activity in in vitro and in vivo experimentsJpn J Pharmacol35203227CrossRefPubMedGoogle Scholar
  24. 24.
    Paques, EP, Romisch, J 1991Comparative study on the in vitro effectiveness of antithrombotic agentsThromb Res641121CrossRefPubMedGoogle Scholar
  25. 25.
    Yoshikawa, T, Murakami, M, Furukawa, Y, Kato, H, Takemura, S, Kondo, M 1983Effects of FUT-175, a new systemic protease inhibitor, on endotoxin-induced disseminated intravascular coagulation in ratsHomeostasis13374378Google Scholar
  26. 26.
    Dixon, B 2004The role of microvascular thrombosis in sepsisAnaesth Intensive Care32619629PubMedGoogle Scholar
  27. 27.
    Uchiba, M, Okajima, K, Murakami, K, Okabe, H, Takatsuki, K 1995Endotoxin-induced pulmonary vascular injury is mainly mediated by activated neutrophils in ratsThromb Res78117125CrossRefPubMedGoogle Scholar
  28. 28.
    Ware, LB, Matthay, MA 2000The acute respiratory distress syndromeN Engl J Med34213341349CrossRefPubMedGoogle Scholar
  29. 29.
    Sugita, H, Ishiko, T, Ikei, S, Hirota, M, Ogawa, M 1999FUT-175 inhibits the production of IL-6 and IL-8 in human monocytesRes Commun Mol Pathol Pharmacol1035764PubMedGoogle Scholar
  30. 30.
    Idell, S 2003Coagulation, fibrinolysis, and fibrin deposition in acute lung injuryCrit Care Med31S213S220CrossRefPubMedGoogle Scholar
  31. 31.
    Mellgren, K, Skogby, M, Friberg, LG, Tengborn, L, Wadenvik, H 1998The influence of a serine protease inhibitor, nafamostat mesilate, on plasma coagulation, and platelet activation during experimental extracorporeal life support (ECLS)Thromb Haemost79342347PubMedGoogle Scholar

Copyright information

© JSA 2007

Authors and Affiliations

  • Satoshi Hagiwara
    • 1
  • Hideo Iwasaka
    • 1
  • Takayuki Noguchi
    • 1
  1. 1.Department of Brain and Nerve Science, AnesthesiologyOita University Faculty of MedicineOitaJapan

Personalised recommendations