Skip to main content

Advertisement

SpringerLink
Log in

Isoflurane inhibits neutrophil recruitment in the cutaneous Arthus reaction model

  • Original Article
  • Published:
Journal of Anesthesia Aims and scope Submit manuscript

Abstract

Purpose

Neutrophil recruitment to the inflammatory sites is regulated by a variety of adhesion molecules including β2 integrins. The dependency of neutrophil recruitment on β2 integrins is variable in different tissues, but has not yet been verified in the cutaneous passive reverse Arthus reaction. We examined this question and also evaluated the impact of isoflurane on neutrophil recruitment to the skin because we previously showed in vitro that isoflurane binds and inhibits β2 integrins.

Methods

The dependency on β2 integrins in neutrophil recruitment to the skin in the Arthus reaction was examined using αL, αM and β2 knockout mice. Then, we evaluated the effect of isoflurane on neutrophil recruitment to the skin. In addition, the effects of isoflurane on neutrophil binding to intercellular adhesion molecule-1 (ICAM-1), one of the β2 integrin ligands, were studied in vitro using cell adhesion assays.

Results

Neutrophil recruitment to the skin in the Arthus reaction model was totally dependent on β2 integrins, as β2 knockout mice completely abolished it. However, the defect of only one of the β2 integrins was not sufficient to abolish neutrophil recruitment. Isoflurane reduced neutrophil recruitment to the skin by approximately 90 %. Also, isoflurane inhibited neutrophil adhesion to β2 integrin ligand ICAM-1.

Conclusions

We demonstrated that (1) neutrophil recruitment to the skin was totally dependent on β2 integrins, and (2) isoflurane significantly impaired neutrophil recruitment. Based on the previous studies on the contribution of other adhesion molecules in neutrophil recruitment, it is likely that isoflurane at least partially affects on β2 integrins in this model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Arhem P, Klement G, Nilsson J. Mechanisms of anesthesia: towards integrating network, cellular, and molecular level modeling. Neuropsychopharmacology. 2003;28(Suppl 1):S40–7.

    Article  PubMed  CAS  Google Scholar 

  2. Eckenhoff RG. Promiscuous ligands and attractive cavities: how do the inhaled anesthetics work? Mol Interv. 2001;1(5):258–68.

    PubMed  CAS  Google Scholar 

  3. Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci. 2008;9(5):370–86.

    Article  PubMed  CAS  Google Scholar 

  4. Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci. 2005;26(10):503–10.

    Article  PubMed  CAS  Google Scholar 

  5. Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. J Anesth. 2008;22(3):263–77.

    Article  PubMed  Google Scholar 

  6. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341(10):738–46.

    Article  PubMed  CAS  Google Scholar 

  7. Williams MR, Azcutia V, Newton G, Alcaide P, Luscinskas FW. Emerging mechanisms of neutrophil recruitment across endothelium. Trends Immunol. 2011;32(10):461–9.

    Article  PubMed  CAS  Google Scholar 

  8. Smith JA. Neutrophils, host defense, and inflammation: a double-edged sword. J Leukoc Biol. 1994;56(6):672–86.

    PubMed  CAS  Google Scholar 

  9. Von Dossow V, Baur S, Sander M, Tonnesen H, Marks C, Paschen C, Berger G, Spies CD. Propofol increased the interleukin-6 to interleukin-10 ratio more than isoflurane after surgery in long-term alcoholic patients. J Int Med Res. 2007;35(3):395–405.

    Google Scholar 

  10. Phillipson M, Kubes P. The neutrophil in vascular inflammation. Nat Med. 2011;17(11):1381–90.

    Article  PubMed  CAS  Google Scholar 

  11. Alon R, Feigelson S. From rolling to arrest on blood vessels: leukocyte tap dancing on endothelial integrin ligands and chemokines at sub-second contacts. Semin Immunol. 2002;14(2):93–104.

    Article  PubMed  CAS  Google Scholar 

  12. Hogg N, Stewart MP, Scarth SL, Newton R, Shaw JM, Law SK, Klein N. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest. 1999;103(1):97–106.

    Google Scholar 

  13. Fischer A, Lisowska-Grospierre B, Anderson DC, Springer TA. Leukocyte adhesion deficiency: molecular basis and functional consequences. Immunodefic Rev. 1988;1(1):39–54.

    PubMed  CAS  Google Scholar 

  14. Etzioni A. Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol. 2010;38(1):54–60.

    Article  PubMed  CAS  Google Scholar 

  15. Ding ZM, Babensee JE, Simon SI, Lu H, Perrard JL, Bullard DC, Dai XY, Bromley SK, Dustin ML, Entman ML, Smith CW, Ballantyne CM. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol. 1999;163(9):5029–38.

    Google Scholar 

  16. de Rossi LW, Horn NA, Buhre W, Gass F, Hutschenreuter G, Rossaint R. The effect of isoflurane on neutrophil selectin and beta(2)-integrin activation in vitro. Anesth Analg. 2002;95(3):583–7 (table of contents).

    Google Scholar 

  17. Yuki K, Astrof NS, Bracken C, Yoo R, Silkworth W, Soriano SG, Shimaoka M. The volatile anesthetic isoflurane perturbs conformational activation of integrin LFA-1 by binding to the allosteric regulatory cavity. FASEB J. 2008;22(12):4109–16.

    Google Scholar 

  18. Yuki K, Bu W, Xi J, Sen M, Shimaoka M, Eckenhoff RG. Isoflurane binds and stabilizes a closed conformation of the leukocyte function-associated antigen-1. FASEB J. 2012.

  19. Zhang H, Astrof NS, Liu JH, Wang JH, Shimaoka M. Crystal structure of isoflurane bound to integrin LFA-1 supports a unified mechanism of volatile anesthetic action in the immune and central nervous systems. FASEB J. 2009;23(8):2735–40.

    Article  PubMed  CAS  Google Scholar 

  20. Scharffetter-Kochanek K, Lu H, Norman K, van Nood N, Munoz F, Grabbe S, McArthur M, Lorenzo I, Kaplan S, Ley K, Smith CW, Montgomery CA, Rich S, Beaudet AL. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med. 1998;188(1):119–31.

    Google Scholar 

  21. Mizgerd JP, Kubo H, Kutkoski GJ, Bhagwan SD, Scharffetter-Kochanek K, Beaudet AL, Doerschuk CM. Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice. J Exp Med. 1997;186(8):1357–64.

    Google Scholar 

  22. Goerge T, Ho-Tin-Noe B, Carbo C, Benarafa C, Remold-O’Donnell E, Zhao BQ, Cifuni SM, Wagner DD. Inflammation induces hemorrhage in thrombocytopenia. Blood. 2008;111(10):4958–64.

    Google Scholar 

  23. Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005;77(5):598–625.

    Article  PubMed  CAS  Google Scholar 

  24. Schultz J, Kaminker K. Myeloperoxidase of the leucocyte of normal human blood. I. Content and localization. Arch Biochem Biophys. 1962;96:465–7.

    Article  PubMed  CAS  Google Scholar 

  25. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982;78(3):206–9.

    Article  PubMed  CAS  Google Scholar 

  26. Rote WE, Dempsey E, Maki S, Vlasuk GP, Moyle M. The role of CD11/CD18 integrins in the reverse passive Arthus reaction in rat dermal tissue. J Leukoc Biol. 1996;59(2):254–61.

    PubMed  CAS  Google Scholar 

  27. Benarafa C, Priebe GP, Remold-O’Donnell E. The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection. J Exp Med. 2007;204(8):1901–9.

    Article  PubMed  CAS  Google Scholar 

  28. Bergmeier W, Goerge T, Wang HW, Crittenden JR, Baldwin AC, Cifuni SM, Housman DE, Graybiel AM, Wagner DD. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest. 2007;117(6):1699–707.

    Google Scholar 

  29. Shimaoka M, Salas A, Yang W, Weitz-Schmidt G, Springer TA. Small molecule integrin antagonists that bind to the beta2 subunit I-like domain and activate signals in one direction and block them in the other. Immunity. 2003;19(3):391–402.

    Article  PubMed  CAS  Google Scholar 

  30. Soehnlein O, Zernecke A, Eriksson EE, Rothfuchs AG, Pham CT, Herwald H, Bidzhekov K, Rottenberg ME, Weber C, Lindbom L. Neutrophil secretion products pave the way for inflammatory monocytes. Blood. 2008;112(4):1461–71.

    Google Scholar 

  31. Soehnlein O, Lindbom L, Weber C. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood. 2009;114(21):4613–23.

    Article  PubMed  CAS  Google Scholar 

  32. Smith RJ, Iden SS, Rohloff NA. A model of Arthus pleurisy: modulation by various pharmacologic and therapeutic agents. Clin Immunol Immunopathol. 1983;26(1):24–34.

    Article  PubMed  CAS  Google Scholar 

  33. Smith CW, Marlin SD, Rothlein R, Toman C, Anderson DC. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest. 1989;83(6):2008–17.

    Article  PubMed  CAS  Google Scholar 

  34. Hentzen ER, Neelamegham S, Kansas GS, Benanti JA, McIntire LV, Smith CW, Simon SI. Sequential binding of CD11a/CD18 and CD11b/CD18 defines neutrophil capture and stable adhesion to intercellular adhesion molecule-1. Blood. 2000;95(3):911–20.

    Google Scholar 

  35. Shimaoka M, Springer TA. Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov. 2003;2(9):703–16.

    Article  PubMed  CAS  Google Scholar 

  36. Kaburagi Y, Hasegawa M, Nagaoka T, Shimada Y, Hamaguchi Y, Komura K, Saito E, Yanaba K, Takehara K, Kadono T, Steeber DA, Tedder TF, Sato S. The cutaneous reverse Arthus reaction requires intercellular adhesion molecule 1 and L-selectin expression. J Immunol. 2002;168(6):2970–8.

    Google Scholar 

  37. Yanaba K, Komura K, Horikawa M, Matsushita Y, Takehara K, Sato S. P-selectin glycoprotein ligand-1 is required for the development of cutaneous vasculitis induced by immune complex deposition. J Leukoc Biol. 2004;76(2):374–82.

    Article  PubMed  CAS  Google Scholar 

  38. Guyer DA, Moore KL, Lynam EB, Schammel CM, Rogelj S, McEver RP, Sklar LA. P-selectin glycoprotein ligand-1 (PSGL-1) is a ligand for L-selectin in neutrophil aggregation. Blood. 1996;88(7):2415–21.

    Google Scholar 

  39. Asa D, Raycroft L, Ma L, Aeed PA, Kaytes PS, Elhammer AP, Geng JG. The P-selectin glycoprotein ligand functions as a common human leukocyte ligand for P- and E-selectins. J Biol Chem. 1995;270(19):11662–70.

    Google Scholar 

  40. Forsyth CB, Solovjov DA, Ugarova TP, Plow EF. Integrin alpha(M)beta(2)-mediated cell migration to fibrinogen and its recognition peptides. J Exp Med. 2001;193(10):1123–33.

    Article  PubMed  CAS  Google Scholar 

  41. Issekutz AC, Issekutz TB. The contribution of LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18) to the in vivo migration of polymorphonuclear leucocytes to inflammatory reactions in the rat. Immunology. 1992;76(4):655–61.

    PubMed  CAS  Google Scholar 

  42. Mayadas TN, Cullere X. Neutrophil beta2 integrins: moderators of life or death decisions. Trends Immunol. 2005;26(7):388–95.

    Article  PubMed  CAS  Google Scholar 

  43. Bratzler DW, Hunt DR. The surgical infection prevention and surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis. 2006;43(3):322–30.

    Article  PubMed  Google Scholar 

  44. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105(4):660–4.

    Article  PubMed  Google Scholar 

  45. Schmits R, Kundig TM, Baker DM, Shumaker G, Simard JJ, Duncan G, Wakeham A, Shahinian A, van der Heiden A, Bachmann MF, Ohashi PS, Mak TW, Hickstein DD. LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor. J Exp Med. 1996;183(4):1415–26.

    Google Scholar 

  46. Lu H, Smith CW, Perrard J, Bullard D, Tang L, Shappell SB, Entman ML, Beaudet AL, Ballantyne CM. LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice. J Clin Invest. 1997;99(6):1340–50.

    Google Scholar 

Download references

Acknowledgments

In part supported by National Institute of Health (NIH) grants HL041002 (D.W.), K08GM101345 (K.Y.) and CHMC Anesthesia Foundation (K.Y.). Acknowledge Dr. Roderic G. Eckenhoff (University of Pennsylvania) for valuable suggestions.

Author information

Authors and Affiliations

  1. Immune Disease Institute, Boston, MA, USA

    Carla Carbo, Koichi Yuki, Melanie Demers, Denisa D. Wagner & Motomu Shimaoka

  2. Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, MA, USA

    Carla Carbo, Melanie Demers, Denisa D. Wagner & Motomu Shimaoka

  3. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Carla Carbo, Melanie Demers & Denisa D. Wagner

  4. Department of Anesthesiology, Perioperative and Pain Medicine, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA, 02115, USA

    Koichi Yuki

  5. Department of Anaesthesia, Harvard Medical School, Boston, MA, USA

    Koichi Yuki & Motomu Shimaoka

  6. Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University, Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Motomu Shimaoka

Authors
  1. Carla Carbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koichi Yuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie Demers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Denisa D. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Motomu Shimaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Koichi Yuki or Motomu Shimaoka.

Additional information

C. Carbo and K. Yuki contributed equally.

About this article

Cite this article

Carbo, C., Yuki, K., Demers, M. et al. Isoflurane inhibits neutrophil recruitment in the cutaneous Arthus reaction model. J Anesth 27, 261–268 (2013). https://doi.org/10.1007/s00540-012-1508-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-012-1508-1

Keywords

Search

Navigation