The major ligand-binding domain (called the α I domain) for β2 integrins is located in the α-subunit.72,74 Integrins undergo dynamic conformational changes, which include the α I domain upon activation (Figure 1A). With extracellular activation of leukocytes, LFA-1 and Mac-1 become active (inside-out signal) (Figure 1B) and then bind to their ligands. This involves the pull-down and unwinding of the α7 helix of the α I domain (“extended conformation”) and conformational rearrangements of the ligand-binding site at the α I domain from a low- to a high-affinity configuration, only the latter of which can tightly bind to ligands (Figure 2). The LFA-1 antagonist lovastatin works by binding to the pocket underneath this α7 helix, impairing ligand binding. Isoflurane and sevoflurane also bind to this “lovastatin site”75–77 and inhibit LFA-1. Mac-1, which is structurally similar to LFA-1, was inhibited by isoflurane but not by sevoflurane.75 We suggest that VAs modulate neutrophil and macrophage recruitment via LFA-1 and/or Mac-1, and phagocytosis via Mac-1, and T cell and B cell recruitment via LFA-1.
Describing the effect of VAs on individual targets in leukocytes does not provide a complete understanding of how VAs affect their function. Bridging the gap between molecular and cellular effects requires an appreciation of how these proteins are integrated within the cell. Although additional VA targets in leukocytes may exist, it is nonetheless important to construct a model of how VAs affect the regulation of leukocyte function. VA target receptors in leukocytes are summarized in Table 6, and here, we review neutrophils, macrophages, and NK cells as examples.
Circulating neutrophils are rapidly primed to extravasate and migrate toward a site of inflammation/infection. During surgery, the time frame of neutrophil recruitment overlaps with the exposure to VAs, making neutrophils prime targets for VA-mediated immunological effects.
Neutrophil recruitment consists of rolling, adhesion, and transmigration. These events are triggered by chemoattractants and inflammatory mediators, which activate neutrophils (inside-out signal) (Figure 1B). The many molecules responsible for neutrophil recruitment have been reviewed elsewhere in detail.73,78 In general, activated neutrophils attach and roll along the endothelium via the selectins (E- and P-selectins on the endothelium and L-selectin on neutrophils). Later, firm adhesion on the endothelium is mediated by the β2 integrins, principally LFA-1 and Mac-1.79 Finally, neutrophils transmigrate through the endothelium to the site of inflammation/infection to mediate a complex array of antibacterial effects, including phagocytosis, generation of toxic reactive oxygen species, secretion of proteases and antimicrobial peptides, neutrophil extracellular traps, as well as mediators that attract additional neutrophils, and macrophages and lymphocytes. The antibacterial products of neutrophils are also responsible for inflammation and tissue destruction encountered during recovery from bacterial infection, sepsis, and ischemia/reperfusion injury.80,81 Phagocytosis of foreign particles/organisms is mediated by complement receptors (such as Mac-1) and Fcγ receptors.82–84
VAs target LFA-1, Mac-1, GlyR, Kv, and Kca channels and NMDA receptors in neutrophils (Table 6). Intracellular calcium serves as a secondary messenger to activate neutrophils, and its concentration is a sensitive indicator of activation.85,86 Intracellular calcium regulates and directly activates β2 integrins (inside-out signal).85 NMDA receptors may enhance intracellular calcium signaling. Potassium efflux via Kv and Kca channels may counterbalance Ca2+ influx, sustaining the resting membrane potential and further enhancing Ca2+ influx as in T cells. The role of Cl− efflux is more clearly understood. Resting neutrophils have an atypically high, intracellular Cl− concentration (80–90 mM).87 Tumor necrosis factor (TNF)-α stimulation causes Cl− efflux in neutrophils. The Cl− inhibitor ethacrynic acid blocks continuous Cl− efflux, cell spreading, and superoxide production in TNF-α-stimulated neutrophils. Furthermore, resuspension of neutrophils in Cl−-free medium results in massive Cl− efflux, Ca2+ influx, enhanced adhesion, and superoxide production, demonstrating that Cl− efflux and Ca2+ influx themselves lead to neutrophil and β2 integrin activation.88 GlyR, however, enhances Cl− influx. Cl− influx hyperpolarizes the cell membrane, which presumably reduces Ca2+ influx27 and the likelihood of neutrophil activation. Figure 2 summarizes the potential effects of VAs on neutrophils.
Macrophages are considered a “professional” phagocyte. Monocytes circulate through bone marrow and extravasate to tissues and differentiate into macrophages.89 Macrophages can be divided into different subsets based on their molecular expression profiles; “classically” activated macrophages are M1 macrophages and “alternatively” activated macrophages are M2 macrophages. M1 macrophages can be induced by interferon-γ and LPS stimulation in vitro, and they mediate host defense with high microbicidal activity, whereas M2 macrophages are induced by interleukin (IL)-4 and IL-13 in vitro and mediate antiinflammatory effect and phagocytosis and help tissue healing.90
NK cells are a phenotypically distinct population of cytotoxic lymphocytes that are critical for innate immunity. They express a number of activating and inhibitory receptors and can respond to a variety of target cells, including viral infected cells and tumor cells, and lyse them without prior immunization.96 The decision to lyse target cells is determined by a delicately balanced input to NK cells from these activating and inhibitory receptors. LFA-1 is one of the critical activating receptors on NK cells involved in binding to target cells (conjugation) and providing signals to lyse target cells.97 The binding of LFA-1 to intercellular adhesion molecule-1 reorganizes cytoskeletal structures within NK cells and causes degranulation and cell lysis.98 An elevation of intracellular calcium is a requisite step for this killing process.99 Potassium channels counterbalance the depolarization induced by a rise of intracellular calcium level55 and have been shown to be involved in the adhesion of NK cells to target cells, as well as cytotoxicity.100 LFA-1, Kca3.1, Kv3.1, and TASK-2 are all receptors that VAs can target in NK cells. Among them, LFA-1 and TASK-2 are both involved in LFA-1-dependent adhesion to target cells.55 A TASK-2 antagonist attenuated calcium influx, preventing depolarization and the release of lytic granules. Similarly, blockade of Kv1.3 reduced calcium influx,55 and thereby NK cell degranulation.56 However, Kca1.3 blockade enhanced the NK degranulation but did not affect attachment to target cells.56 The summary is in Figure 4, demonstrating the various potential effects of VAs on NK cell functions.
Our body has multilayered defense mechanisms against the outside world. Skin and mucosa are the most exposed tissues and act as the first line of defense against various organisms. Surgical procedures usually disrupt these barriers and introduce various organisms to otherwise sterile sites. Also tissue injury itself triggers acute inflammation (“sterile inflammation”). Adequate recruitment of circulating leukocytes to the site is critical for cleaning the site and promoting wound healing. In addition, some surgical procedures involve more extreme forms of pathophysiology such as ischemia-reperfusion. During tumor resection, immune cells may have to keep fighting to eradicate disseminated tumor cells. The role of VAs in these circumstances is briefly reviewed.
Ischemia-reperfusion is a common experience in many surgical procedures (eg, Pringle maneuver, unclamping of cross-clamped arteries, reestablishment of blood flow during transplantation) or after relief of vascular obstruction (eg, relieving malrotation of guts, embolectomy). This is considered an extreme example of sterile inflammation. Among immune cells, neutrophil recruitment plays a central role in the pathogenesis,101,102 and the activation of β2 integrins is critical. The benefit of VAs in ischemia-reperfusion has been shown in various organs and tissues including kidney,103 lung,104 and coronary artery/ myocardium in animal models.102,105 In a study using healthy human volunteers, sevoflurane (even at 0.5%–1%) protected forearm ischemia-reperfusion injury via an attenuation of neutrophil activation.106 The benefit of VAs in clinical settings is also reported in cardiac surgery.107 These results, while sparse, support a role for VAs in mitigating sterile inflammation.
Although surgical resection is considered a gold standard of solid tumor management, recurrence or metastasis remains the major cause of death.108 The postulated, underlying mechanisms include the mechanical dissemination of tumor cells intraoperatively and promotion of local and distal metastasis by attenuation of cell-mediated immunity.109 A growing literature suggests that the type of anesthesia/anesthetics is associated with the frequency of tumor recurrence or metastasis. In general, less general anesthesia is associated with less recurrence or metastasis, or better outcomes110–114 and these studies were previously reviewed in detail.115 A recent retrospective study showed that patients receiving VAs for their surgery were associated with a hazard ratio of 1.59 for death on the univariate analysis and 1.46 after the multivariate analysis compared with the patients receiving total IV anesthesia, suggesting that VAs may not be beneficial in tumor surgery.116 Perioperative NK cell suppression correlates with higher recurrence and mortality in patients.117,118 As stated earlier, VAs should impair NK conjugation and degranulation via inhibiting LFA-1 and TASK-2. However, VAs could enhance degranulation through their interaction with Kca3.1 and Kv1.3. Given that conjugation precedes degranulation, VAs presumably impair NK cell cytotoxicity, but further study is warranted to confirm these provocative findings.
Perioperative infection is one of the most common perioperative complications. Von Dossow et al119 examined alcoholic patients who underwent resection of upper gastrointestinal tract under general anesthesia either with propofol or isoflurane. Postoperative infection rate was lower in the propofol group (23%) than in the isoflurane group (67%). Chang et al120 studied the incidence of surgical site infection in patients who underwent orthopedic procedures under regional anesthesia (spinal or epidural anesthesia) or general anesthesia and found that the general anesthesia arm had a higher incidence of surgical site infection (2.8%) over the regional anesthesia arm (1.2%). Although the detailed information of the general anesthetics was not reported, VAs would presumably be the major anesthetics in their general anesthesia group. Leukocyte recruitment and subsequent killing of microbes are required to minimize perioperative infection. Several animal studies have demonstrated that VAs modify leukocyte adhesion and recruitment.71,105,121–126 The number of recruited leukocytes to tissues is determined by a balance between proinflammatory signals and antiinflammatory signals (resolution). The intravital microscopic experiment of mesenteric circulation in LPS-induced inflammation showed that isoflurane exposure increased the speed of leukocyte rolling,122 which could lead to impaired adhesion and transmigration. Our study using the reverse Arthus reaction model in mice showed impaired neutrophil migration by isoflurane.70 Although the proinflammatory mediators in these models recruit leukocytes, resolution agonists such as lipoxins and resolvins limit further recruitment,127 but the effect of VAs on resolution agonists was not reported.126 The role of VAs on bacterial killing has also been studied. Ex vivo studies in patients (ASA physical status I–III) undergoing abdominal surgery showed a reduction of granulocyte phagocytosis and oxidative burst after 1 hour of sevoflurane or xenon anesthesia.128 Also in an ex vivo study using patients who underwent orthopedic procedures, a time-dependent reduction of phagocytic function and bacterial killing was reported to occur under isoflurane anesthesia.129
Change in personality or cognitive ability after surgery is considered a significant form of morbidity. The causes are likely multifactorial, including a host of preoperative comorbidities, and inflammation, stress, and infection resulting from surgery and anesthesia. TNF-α and its downstream mediator IL-1β play a role in cognitive dysfunction in animal models.130,131 Cognitive dysfunction produced by TNF-α/IL-1β in mice occurred via the α5GABAA receptor. Activation of this receptor appears to impair memory and IL-1β-induced prolonged α5GABAA receptor expression.132 Furthermore, isoflurane caused a persistent tonic current via α5GABAA receptor.133
Microglia, which are analogous to macrophages in the brain, secrete a variety of proinflammatory mediators, so attenuating this neuroinflammation may help to reduce postoperative memory and perhaps cognitive deficits. In a study of isolated microglia, isoflurane had little effect on LPS-stimulated proinflammatory cytokine release, while sevoflurane enhanced it.134 In patients undergoing esophageal tumor resection under sevoflurane anesthesia or propofol anesthesia, cognitive decline was more apparent in the sevoflurane anesthesia group and was associated with higher plasma IL-6 and TNF-α concentrations. Finally, in a rare randomized controlled study of older patients getting spinal surgery, and with mild preexisting cognitive deficits, those receiving sevoflurane anesthesia declined more rapidly compared with regional or propofol.135 These studies suggest that VAs may contribute to postoperative cognitive decline, but it is becoming clear that many other factors are involved.
Although clinical studies on the association between VAs and immunological issues are limited, this review highlights a molecular biological basis of VA-induced immunomodulation and hopefully facilitates clinical studies on perioperative immunological outcomes in the future.
1. Eckenhoff RG. Promiscuous ligands and attractive cavities: how do the inhaled anesthetics work? Mol Interv. 2001;1:258–68.
2. Gaylord H, Simpson BT. The effect of certain anesthetics and loss of blood upon the growth of transplanted mouse cancer. J Cancer Res 1916;1:379–82.
3. Graham E. The influence of ether and ether anesthesia on bacteriolysis, agglutination, and phagocytosis. J Infect Dis 1911;8:147–75.
4. Olsen RW, Tobin AJ. Molecular biology of GABAA receptors. FASEB J 1990;4:1469–80.
5. Goetz T, Arslan A, Wisden W, Wulff P. GABA(A) receptors: structure and function in the basal ganglia. Prog Brain Res 2007;160:21–41.
6. Garcia PS, Kolesky SE, Jenkins A. General anesthetic actions on GABA(A) receptors. Curr Neuropharmacol 2010;8:2–9.
7. Verkman AS, Galietta LJ. Chloride channels as drug targets. Nat Rev Drug Discov 2009;8:153–71.
8. Nishikawa K, Harrison NL. The actions of sevoflurane and desflurane on the gamma-aminobutyric acid receptor type A: effects of TM2 mutations in the alpha and beta subunits. Anesthesiology 2003;99:678–84.
9. Sonner JM, Cascio M, Xing Y, Fanselow MS, Kralic JE, Morrow AL, Korpi ER, Hardy S, Sloat B, Eger EI II, Homanics GE. Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear. Mol Pharmacol 2005;68:61–8.
10. Werner DF, Swihart A, Rau V, Jia F, Borghese CM, McCracken ML, Iyer S, Fanselow MS, Oh I, Sonner JM, Eger EI II, Harrison NL, Harris RA, Homanics GE. Inhaled anesthetic responses of recombinant receptors and knockin mice harboring α2(S270H/L277A) GABA(A) receptor subunits that are resistant to isoflurane. J Pharmacol Exp Ther 2011;336:134–44.
11. Schofield CM, Harrison NL. Transmembrane residues define the action of isoflurane at the GABAA receptor alpha-3 subunit. Brain Res 2005;1032:30–5.
12. Jia F, Yue M, Chandra D, Homanics GE, Goldstein PA, Harrison NL. Isoflurane is a potent modulator of extrasynaptic GABA(A) receptors in the thalamus. J Pharmacol Exp Ther 2008;324:1127–35.
13. Caraiscos VB, Newell JG, You-Ten KE, Elliott EM, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane. J Neurosci 2004;24:8454–8.
14. Lecker I, Yin Y, Wang DS, Orser BA. Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists. Br J Anaesth 2013;110(suppl 1):i73–81.
15. Rau V, Oh I, Liao M, Bodarky C, Fanselow MS, Homanics GE, Sonner JM, Eger EI II. Gamma-aminobutyric acid type A receptor β3 subunit forebrain-specific knockout mice are resistant to the amnestic effect of isoflurane. Anesth Analg 2011;113:500–4.
16. Alam S, Laughton DL, Walding A, Wolstenholme AJ. Human peripheral blood mononuclear cells express GABAA receptor subunits. Mol Immunol 2006;43:1432–42.
17. Dionisio L, José De Rosa M, Bouzat C, Esandi Mdel C. An intrinsic GABAergic system in human lymphocytes. Neuropharmacology 2011;60:513–9.
18. Wheeler DW, Thompson AJ, Corletto F, Reckless J, Loke JC, Lapaque N, Grant AJ, Mastroeni P, Grainger DJ, Padgett CL, O’Brien JA, Miller NG, Trowsdale J, Lummis SC, Menon DK, Beech JS. Anaesthetic impairment of immune function is mediated via GABA(A) receptors. PLoS One 2011;6:e17152.
19. Jin Z, Mendu SK, Birnir B. GABA is an effective immunomodulatory molecule. Amino Acids 2013;45:87–94.
20. Tian J, Chau C, Hales TG, Kaufman DL. GABA(A) receptors mediate inhibition of T cell responses. J Neuroimmunol 1999;96:21–8.
21. Tian J, Lu Y, Zhang H, Chau CH, Dang HN, Kaufman DL. Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. J Immunol 2004;173:5298–304.
22. Betz H, Laube B. Glycine receptors: recent insights into their structural organization and functional diversity. J Neurochem 2006;97:1600–10.
23. Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 2004;84:1051–95.
24. Downie DL, Hall AC, Lieb WR, Franks NP. Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurones and recombinant glycine receptors in Xenopus oocytes. Br J Pharmacol 1996;118:493–502.
25. Harrison NL, Kugler JL, Jones MV, Greenblatt EP, Pritchett DB. Positive modulation of human gamma-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane. Mol Pharmacol 1993;44:628–32.
26. Froh M, Thurman RG, Wheeler MD. Molecular evidence for a glycine-gated chloride channel in macrophages and leukocytes. Am J Physiol Gastrointest Liver Physiol 2002;283:G856–63.
27. Wheeler M, Stachlewitz RF, Yamashina S, Ikejima K, Morrow AL, Thurman RG. Glycine-gated chloride channels in neutrophils attenuate calcium influx and superoxide production. FASEB J 2000;14:476–84.
28. Spittler A, Reissner CM, Oehler R, Gornikiewicz A, Gruenberger T, Manhart N, Brodowicz T, Mittlboeck M, Boltz-Nitulescu G, Roth E. Immunomodulatory effects of glycine on LPS-treated monocytes: reduced TNF-alpha production and accelerated IL-10 expression. FASEB J 1999;13:563–71.
29. Wheeler MD, Thurman RG. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Am J Physiol 1999;277:L952–9.
30. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8.
31. van der Zanden EP, Snoek SA, Heinsbroek SE, Stanisor OI, Verseijden C, Boeckxstaens GE, Peppelenbosch MP, Greaves DR, Gordon S, De Jonge WJ. Vagus nerve activity augments intestinal macrophage phagocytosis via nicotinic acetylcholine receptor alpha4beta2. Gastroenterology 2009;137:1029–39, 1039.e14.
32. Nemethova A, Michel K, Gomez-Pinilla PJ, Boeckxstaens GE, Schemann M. Nicotine attenuates activation of tissue resident macrophages in the mouse stomach through the β2 nicotinic acetylcholine receptor. PLoS One 2013;8:e79264.
33. Skok MV, Grailhe R, Agenes F, Changeux JP. The role of nicotinic receptors in B-lymphocyte development and activation. Life Sci 2007;80:2334–6.
34. Su X, Matthay MA, Malik AB. Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J Immunol 2010;184:401–10.
35. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology 1997;86:859–65.
36. Violet JM, Downie DL, Nakisa RC, Lieb WR, Franks NP. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology 1997;86:866–74.
37. Yamashita M, Mori T, Nagata K, Yeh JZ, Narahashi T. Isoflurane modulation of neuronal nicotinic acetylcholine receptors expressed in human embryonic kidney cells. Anesthesiology 2005;102:76–84.
38. Downie DL, Vicente-Agullo F, Campos-Caro A, Bushell TJ, Lieb WR, Franks NP. Determinants of the anesthetic sensitivity of neuronal nicotinic acetylcholine receptors. J Biol Chem 2002;277:10367–73.
39. Fulcher DA, Basten A. B cell life span: a review. Immunol Cell Biol 1997;75:446–55.
40. Kelly-Scumpia KM, Scumpia PO, Weinstein JS, Delano MJ, Cuenca AG, Nacionales DC, Wynn JL, Lee PY, Kumagai Y, Efron PA, Akira S, Wasserfall C, Atkinson MA, Moldawer LL. B cells enhance early innate immune responses during bacterial sepsis. J Exp Med 2011;208:1673–82.
41. Ahern GP. 5-HT and the immune system. Curr Opin Pharmacol 2011;11:29–33.
42. Surmiak M, Kaczor M, Sanak M. Expression profile of proinflammatory genes in neutrophil-enriched granulocytes stimulated with native anti-PR3 autoantibodies. J Physiol Pharmacol 2012;63:249–56.
43. Nakamura K, Sato T, Ohashi A, Tsurui H, Hasegawa H. Role of a serotonin precursor in development of gut microvilli. Am J Pathol 2008;172:333–44.
44. Matsunaga F, Gao L, Huang XP, Saven JG, Roth BL, Liu R. Molecular interactions between general anesthetics and the 5HT2B receptor. J Biomol Struct Dyn 2015;33:211–8.
45. Mayer ML, Armstrong N. Structure and function of glutamate receptor ion channels. Annu Rev Physiol 2004;66:161–81.
46. Boldyrev AA, Kazey VI, Leinsoo TA, Mashkina AP, Tyulina OV, Johnson P, Tuneva JO, Chittur S, Carpenter DO. Rodent lymphocytes express functionally active glutamate receptors. Biochem Biophys Res Commun 2004;324:133–9.
47. Miglio G, Varsaldi F, Lombardi G. Human T lymphocytes express N-methyl-D-aspartate receptors functionally active in controlling T cell activation. Biochem Biophys Res Commun 2005;338:1875–83.
48. Miglio G, Dianzani C, Fallarini S, Fantozzi R, Lombardi G. Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to fibronectin. Biochem Biophys Res Commun 2007;361:404–9.
49. Bryushkova EA, Vladychenskaya EA, Stepanova MS, Boldyrev AA. Effect of homocysteine on properties of neutrophils activated in vivo. Biochemistry (Mosc) 2011;76:467–72.
50. Hollmann MW, Liu HT, Hoenemann CW, Liu WH, Durieux ME. Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics. Anesth Analg 2001;92:1182–91.
51. Ogata J, Shiraishi M, Namba T, Smothers CT, Woodward JJ, Harris RA. Effects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 2006;318:434–43.
52. Franks NP, Honoré E. The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci 2004;25:601–8.
53. Stadnicka A, Bosnjak ZJ, Kampine JP, Kwok WM. Modulation of cardiac inward rectifier K(+)current by halothane and isoflurane. Anesth Analg 2000;90:824–33.
54. Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol 2015;33:291–353.
55. Schulte-Mecklenbeck A, Bittner S, Ehling P, Döring F, Wischmeyer E, Breuer J, Herrmann AM, Wiendl H, Meuth SG, Gross CC. The two-pore domain K2 P channel TASK2 drives human NK-cell proliferation and cytolytic function. Eur J Immunol 2015;45:2602–14.
56. Koshy S, Wu D, Hu X, Tajhya RB, Huq R, Khan FS, Pennington MW, Wulff H, Yotnda P, Beeton C. Blocking KCa3.1 channels increases tumor cell killing by a subpopulation of human natural killer lymphocytes. PLoS One 2013;8:e76740.
57. Krause KH, Welsh MJ. Voltage-dependent and Ca2(+)-activated ion channels in human neutrophils. J Clin Invest 1990;85:491–8.
58. Lioudyno MI, Birch AM, Tanaka BS, Sokolov Y, Goldin AL, Chandy KG, Hall JE, Alkire MT. Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci 2013;33:16310–22.
59. Meuth SG, Bittner S, Meuth P, Simon OJ, Budde T, Wiendl H. TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 critically influence T lymphocyte effector functions. J Biol Chem 2008;283:14559–70.
60. Bittner S, Bobak N, Herrmann AM, Göbel K, Meuth P, Höhn KG, Stenner MP, Budde T, Wiendl H, Meuth SG. Upregulation of K2P5.1 potassium channels in multiple sclerosis. Ann Neurol 2010;68:58–69.
61. Liu C, Au JD, Zou HL, Cotten JF, Yost CS. Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth Analg 2004;99:1715–22.
62. Patel AJ, Honoré E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 1999;2:422–6.
63. Putzke C, Hanley PJ, Schlichthörl G, Preisig-Müller R, Rinné S, Anetseder M, Eckenhoff R, Berkowitz C, Vassiliou T, Wulf H, Eberhart L. Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1. Am J Physiol Cell Physiol 2007;293:C1319–26.
64. Gray AT, Zhao BB, Kindler CH, Winegar BD, Mazurek MJ, Xu J, Chavez RA, Forsayeth JR, Yost CS. Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5. Anesthesiology 2000;92:1722–30.
65. Meadows HJ, Randall AD. Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel. Neuropharmacology 2001;40:551–9.
66. OuYang W, Hemmings HC Jr. Isoform-selective effects of isoflurane on voltage-gated Na+ channels. Anesthesiology 2007;107:91–8.
67. Carrithers MD, Dib-Hajj S, Carrithers LM, Tokmoulina G, Pypaert M, Jonas EA, Waxman SG. Expression of the voltage-gated sodium channel NaV1.5 in the macrophage late endosome regulates endosomal acidification. J Immunol 2007;178:7822–32.
68. Carrithers LM, Hulseberg P, Sandor M, Carrithers MD. The human macrophage sodium channel NaV1.5 regulates mycobacteria processing through organelle polarization and localized calcium oscillations. FEMS Immunol Med Microbiol 2011;63:319–27.
69. Lo WL, Donermeyer DL, Allen PM. A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells. Nat Immunol 2012;13:880–7.
70. Carbo C, Yuki K, Demers M, Wagner DD, Shimaoka M. Isoflurane inhibits neutrophil recruitment in the cutaneous Arthus reaction model. J Anesth 2013;27:261–8.
71. Möbert J, Zahler S, Becker BF, Conzen PF. Inhibition of neutrophil activation by volatile anesthetics decreases adhesion to cultured human endothelial cells. Anesthesiology 1999;90:1372–81.
72. Shimaoka M, Takagi J, Springer TA. Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct 2002;31:485–516.
73. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013;13:159–75.
74. Diamond MS, Garcia-Aguilar J, Bickford JK, Corbi AL, Springer TA. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands. J Cell Biol 1993;120:1031–43.
75. 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;22:4109–16.
76. Yuki K, Astrof NS, Bracken C, Soriano SG, Shimaoka M. Sevoflurane binds and allosterically blocks integrin lymphocyte function-associated antigen-1. Anesthesiology 2010;113:600–9.
77. 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;26:4408–17.
78. Wagner DD, Frenette PS. The vessel wall and its interactions. Blood 2008;111:5271–81.
79. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301–14.
80. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989;320:365–76.
81. De Greef KE, Ysebaert DK, Ghielli M, Vercauteren S, Nouwen EJ, Eyskens EJ, De Broe ME. Neutrophils and acute ischemia-reperfusion injury. J Nephrol 1998;11:110–22.
82. Thelen M, Didichenko SA. G-protein coupled receptor-mediated activation of PI 3-kinase in neutrophils. Ann N Y Acad Sci 1997;832:368–82.
83. Arnaout MA, Melamed J, Tack BF, Colten HR. Characterization of the human complement (c3b) receptor with a fluid phase C3b dimer. J Immunol 1981;127:1348–54.
84. Lanier LL, Arnaout MA, Schwarting R, Warner NL, Ross GD. p150/95, Third member of the LFA-1/CR3 polypeptide family identified by anti-Leu M5 monoclonal antibody. Eur J Immunol 1985;15:713–8.
85. Schaff UY, Yamayoshi I, Tse T, Griffin D, Kibathi L, Simon SI. Calcium flux in neutrophils synchronizes beta2 integrin adhesive and signaling events that guide inflammatory recruitment. Ann Biomed Eng 2008;36:632–46.
86. Bréchard S, Tschirhart EJ. Regulation of superoxide production in neutrophils: role of calcium influx. J Leukoc Biol 2008;84:1223–37.
87. Simchowitz L, De Weer P. Chloride movements in human neutrophils. Diffusion, exchange, and active transport. J Gen Physiol 1986;88:167–94.
88. Menegazzi R, Busetto S, Dri P, Cramer R, Patriarca P. Chloride ion efflux regulates adherence, spreading, and respiratory burst of neutrophils stimulated by tumor necrosis factor-alpha (TNF) on biologic surfaces. J Cell Biol 1996;135:511–22.
89. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011;11:723–37.
90. Vogel DY, Heijnen PD, Breur M, de Vries HE, Tool AT, Amor S, Dijkstra CD. Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation. J Neuroinflammation 2014;11:23.
91. Reyes-García MG, Hernández-Hernández F, Hernández-Téllez B, García-Tamayo F. GABA (A) receptor subunits RNA expression in mice peritoneal macrophages modulate their IL-6/IL-12 production. J Neuroimmunol 2007;188:64–8.
92. Moreno C, Prieto P, Macías Á, Pimentel-Santillana M, de la Cruz A, Través PG, Boscá L, Valenzuela C. Modulation of voltage-dependent and inward rectifier potassium channels by 15-epi-lipoxin-A4 in activated murine macrophages: implications in innate immunity. J Immunol 2013;191:6136–46.
93. Chung I, Zelivyanskaya M, Gendelman HE. Mononuclear phagocyte biophysiology influences brain transendothelial and tissue migration: implication for HIV-1-associated dementia. J Neuroimmunol 2002;122:40–54.
94. Toyama K, Wulff H, Chandy KG, Azam P, Raman G, Saito T, Fujiwara Y, Mattson DL, Das S, Melvin JE, Pratt PF, Hatoum OA, Gutterman DD, Harder DR, Miura H. The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to atherogenesis in mice and humans. J Clin Invest 2008;118:3025–37.
95. Freire-Garabal M, Núñez MJ, Balboa J, López-Delgado P, Gallego R, García-Caballero T, Fernández-Roel MD, Brenlla J, Rey-Méndez M. Serotonin upregulates the activity of phagocytosis through 5-HT1A receptors. Br J Pharmacol 2003;139:457–63.
96. Topham NJ, Hewitt EW. Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 2009;128:7–15.
97. Thomas LM, Peterson ME, Long EO. Cutting edge: NK cell licensing modulates adhesion to target cells. J Immunol 2013;191:3981–5.
98. Barber DF, Faure M, Long EO. LFA-1 contributes an early signal for NK cell cytotoxicity. J Immunol 2004;173:3653–9.
99. Schwarz EC, Qu B, Hoth M. Calcium, cancer and killing: the role of calcium in killing cancer cells by cytotoxic T lymphocytes and natural killer cells. Biochim Biophys Acta 2013;1833:1603–11.
100. Sidell N, Schlichter LC, Wright SC, Hagiwara S, Golub SH. Potassium channels in human NK cells are involved in discrete stages of the killing process. J Immunol 1986;137:1650–8.
101. Yago T, Petrich BG, Zhang N, Liu Z, Shao B, Ginsberg MH, McEver RP. Blocking neutrophil integrin activation prevents ischemia-reperfusion injury. J Exp Med 2015;212:1267–81.
102. Kowalski C, Zahler S, Becker BF, Flaucher A, Conzen PF, Gerlach E, Peter K. Halothane, isoflurane, and sevoflurane reduce postischemic adhesion of neutrophils in the coronary system. Anesthesiology 1997;86:188–95.
103. Lee HT, Ota-Setlik A, Fu Y, Nasr SH, Emala CW. Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo. Anesthesiology 2004;101:1313–24.
104. Liu R, Ishibe Y, Ueda M. Isoflurane-sevoflurane administration before ischemia attenuates ischemia-reperfusion-induced injury in isolated rat lungs. Anesthesiology 2000;92:833–40.
105. Heindl B, Reichle FM, Zahler S, Conzen PF, Becker BF. Sevoflurane and isoflurane protect the reperfused guinea pig heart by reducing postischemic adhesion of polymorphonuclear neutrophils. Anesthesiology 1999;91:521–30.
106. Lucchinetti E, Ambrosio S, Aguirre J, Herrmann P, Härter L, Keel M, Meier T, Zaugg M. Sevoflurane inhalation at sedative concentrations provides endothelial protection against ischemia-reperfusion injury in humans. Anesthesiology 2007;106:262–8.
107. Conzen PF, Fischer S, Detter C, Peter K. Sevoflurane provides greater protection of the myocardium than propofol in patients undergoing off-pump coronary artery bypass surgery. Anesthesiology 2003;99:826–33.
108. Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg 2010;110:1636–43.
109. Tavare AN, Perry NJ, Benzonana LL, Takata M, Ma D. Cancer recurrence after surgery: direct and indirect effects of anesthetic agents. Int J Cancer 2012;130:1237–50.
110. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;105:660–4.
111. Christopherson R, James KE, Tableman M, Marshall P, Johnson FE. Long-term survival after colon cancer surgery: a variation associated with choice of anesthesia. Anesth Analg 2008;107:325–32.
112. Schlagenhauff B, Ellwanger U, Breuninger H, Stroebel W, Rassner G, Garbe C. Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma. Melanoma Res 2000;10:165–9.
113. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 2008;109:180–7.
114. Lin L, Liu C, Tan H, Ouyang H, Zhang Y, Zeng W. Anaesthetic technique may affect prognosis for ovarian serous adenocarcinoma: a retrospective analysis. Br J Anaesth 2011;106:814–22.
115. Heaney A, Buggy DJ. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Br J Anaesth 2012;109(suppl 1):i17–28.
116. Wigmore TJ, Mohammed K, Jhanji S. Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery: a retrospective analysis. Anesthesiology 2016;124:69–79.
117. Tartter PI, Steinberg B, Barron DM, Martinelli G. The prognostic significance of natural killer cytotoxicity in patients with colorectal cancer. Arch Surg 1987;122:1264–8.
118. Fujisawa T, Yamaguchi Y. Autologous tumor killing activity as a prognostic factor in primary resected nonsmall cell carcinoma of the lung. Cancer 1997;79:474–81.
119. Von Dossow V, Baur S, Sander M, Tønnesen 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;35:395–405.
120. Chang CC, Lin HC, Lin HW, Lin HC. Anesthetic management and surgical site infections in total hip or knee replacement: a population-based study. Anesthesiology 2010;113:279–84.
121. McBride WT, Armstrong MA, McBride SJ. Immunomodulation: an important concept in modern anaesthesia. Anaesthesia 1996;51:465–73.
122. Hayes JK, Havaleshko DM, Plachinta RV, Rich GF. Isoflurane pretreatment supports hemodynamics and leukocyte rolling velocities in rat mesentery during lipopolysaccharide-induced inflammation. Anesth Analg 2004;98:999–1006.
123. Reutershan J, Chang D, Hayes JK, Ley K. Protective effects of isoflurane pretreatment in endotoxin-induced lung injury. Anesthesiology 2006;104:511–7.
124. Lee HT, Kim M, Kim N, Billings FT IV, D’Agati VD, Emala CW Sr. Isoflurane protects against renal ischemia and reperfusion injury and modulates leukocyte infiltration in mice. Am J Physiol Renal Physiol 2007;293:F713–22.
125. Lee HT, Emala CW, Joo JD, Kim M. Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis. Shock 2007;27:373–9.
126. Chiang N, Schwab JM, Fredman G, Kasuga K, Gelman S, Serhan CN. Anesthetics impact the resolution of inflammation. PLoS One 2008;3:e1879.
127. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008;8:349–61.
128. Fahlenkamp AV, Coburn M, Rossaint R, Stoppe C, Haase H. Comparison of the effects of xenon and sevoflurane anaesthesia on leucocyte function in surgical patients: a randomized trial. Br J Anaesth 2014;112:272–80.
129. Kotani N, Hashimoto H, Sessler DI, Kikuchi A, Suzuki A, Takahashi S, Muraoka M, Matsuki A. Intraoperative modulation of alveolar macrophage function during isoflurane and propofol anesthesia. Anesthesiology 1998;89:1125–32.
130. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A 2010;107:20518–22.
131. Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010;68:360–8.
132. Wang DS, Zurek AA, Lecker I, Yu J, Abramian AM, Avramescu S, Davies PA, Moss SJ, Lu WY, Orser BA. Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors. Cell Rep 2012;2:488–96.
133. Zurek AA, Yu J, Wang DS, Haffey SC, Bridgwater EM, Penna A, Lecker I, Lei G, Chang T, Salter EW, Orser BA. Sustained increase in α5GABAA receptor function impairs memory after anesthesia. J Clin Invest 2014;124:5437–41.
134. Ye X, Lian Q, Eckenhoff MF, Eckenhoff RG, Pan JZ. Differential general anesthetic effects on microglial cytokine expression. PLoS One 2013;8:e52887.
135. Liu Y, Pan N, Ma Y, Zhang S, Guo W, Li H, Zhou J, Liu G, Gao M. Inhaled sevoflurane may promote progression of amnestic mild cognitive impairment: a prospective, randomized parallel-group study. Am J Med Sci 2013;345:355–60.