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Immunomodulation in perioperative medicine “We have not clinically applied our extensive knowledge of the mediators of acute inflammation to alter the response within an injured tissue, to reduce local edema and pain, or promote wound healing. Perioperative administration of an IL‑1 inhibitor would represent an important step towards developing this approach.” Gary Peltz† Although the basic outline of the biology underlying the multiphasic mammalian wound response is well known [1] , we do not know how to design interventions that reduce incisional pain and accelerate wound healing in the perioperative period, which would improve surgical outcome consider­ ably [2] . The complexity of the wound heal­ ing response has made it difficult to iden­ tify the pathways and mediators to target for therapeutic intervention. For example, the level of expression of over 1000 genes is significantly altered within the very narrow margins around the wound edge shortly after wounding  [3] . Furthermore, differ­ ent experimental approaches for studying wound biology have produced conflicting results. Although it is believed that macro­ phages and mast cells produce cytokines and growth factors that are essential for wound healing [4] , gene knockout mice that are essentially devoid of mast cells [5] , or macro­phages and neutrophils [6] , have normal wound healing. Similarly, delays in several wound healing parameters were noted in mice with a gene knockout of a par­ ticular chemokine [7] or its corresponding receptor [8] ; yet wound-healing para­meters were not altered in experiments where this chemokine was directly introduced into

incisional wounds [9] . Different experi­ mental systems have supported completely divergent therapeutic approaches. Our findings My group have utilized a mouse genetic approach to analyze wound biology [10] . We have previously used this approach to understand complicated biomedical responses [11] and have found it especially useful when conventional studies have produced conflicting data. To do this, full-thickness incisional wounds were made in 16 inbred mouse strains, and the levels of multiple inflammatory mediators produced within these wounds were meas­ ured. We found very large (75–463‑fold) interstrain differences in the level of two inf lam­m atory chemokines produced within wound tissue [10] . Genetic variation within a gene that regulated IL‑1 produc­ tion correlated with these interstrain dif­ ferences. This correlation was consistent with IL‑1a- or IL‑1b-stimulated chemo­ kine production by murine and human cell lines in vitro  [10,12] . A well-characterized murine model of incisional wounding was used to assess the in vivo role of IL‑1 in wound bio­logy. Administration of an IL‑1 receptor antagonist (IL‑1ra) to mice

“Although the basic outline of

the biology underlying the multiphasic mammalian wound response is well known … we do not know how to design interventions that reduce incisional pain and accelerate wound healing in the perioperative period, which would improve surgical outcome considerably…”

Department of Anesthesia, Stanford University, 800 Welch Road, Room 213, Stanford, CA 94305, USA; Tel.: +1 650 721 2487; Fax: +1 650 721 2420; [email protected]

10.2217/PMT.11.5 © 2011 Future Medicine Ltd

Pain Manage. (2011) 1(2), 103–106

ISSN 1758-1869

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Editorial  Peltz decreased the nociceptive response after inci­ sional wounding and reduced the production of multiple inflammatory mediators, includ­ ing TNF‑a, IL‑6 and multiple chemokines (macrophage inflam­matory protein [MIP]‑1a and murine homologs of IL‑8) in wounds [12] . In addition, IL‑1b and IL‑8 levels were highly correlated in human surgical wounds and at cutaneous sites of human UVB-induced sun­ burn. These results led to a revised model for the incisional wound response: IL‑1 is a ‘master regulator’ of the production of inflammatory mediators in wounds, which are linked with nociception [12] .

“…it is possible that surgical outcomes could be improved by perioperative immunomodulation, and this could become a standard part of pain management for surgeries performed in the 21st century.”

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A new approach: risk versus benefit Our study suggested that perioperative admin­ istration of an IL‑1ra could decrease incisional inflammation and pain. The IL‑1ra used in these studies (anakinra) is the recombinant form of a naturally occurring 153‑amino acid protein that competitively inhibits IL‑1 binding to its receptor, and is a readily available medication that has been approved for the treatment of rheumatoid arthritis. Anakinra has a good safety record, even when administered for a period of 3 years [13,14] . The usual dose of IL‑1ra is 100 mg sub­cutaneously, once daily, its terminal half-life ranges from 4 to 6 h and it is primarily (~80%) cleared through renal excretion [15] . Our study suggests that a brief period of administration of an IL‑1 inhibitor could have significant benefits in the perioperative setting. However, two critical concerns regarding this approach must be addressed: will this treatment have an adverse effect on wound healing or cause an increase in the rate of infection? Existing ani­ mal model data indicate that wound healing will not be impaired, and it may even be facilitated. Wound healing has been demonstrated in vivo to be improved in IL‑1 receptor knockout mice [16] and impaired in IL‑1ra knockout mice [17] . Furthermore, periodontal wound healing was improved after IL‑1 inhibitor administration for 3 or 14 days in a primate model [18] . Although the significance of in vitro results can be difficult to assess, it is worth noting that acute exposure to exogenous IL‑1 reduced the level of repair of an injured meniscus [19] . While it is important to monitor patients for infection, IL‑1 inhibition for a brief period would not be expected to increase the risk of infection in the perioperative period in most cir­ cumstances. In one study, a higher rate of serious

Pain Manage. (2011) 1(2)

infections was noted in rheumatoid arthritis patients who were treated with IL‑1ra for up to 3 years [14] . However, the serious infection rate was substantially affected by whether the patient was receiving corticosteroid treatment in that study, and a meta-analysis of five trials covering 2846 patients indicated that IL‑1ra treatment did not cause a statistically significant increase in the number of (total and serious) infections [13] . IL‑1 inhibition should be avoided when deal­ ing with potentially contaminated or infected wounds, when treating immunocompromised patients, if the patient is being treated with a TNF inhibitor [20] , or if there is evidence of (or risk for) a serious infection such as tuberculosis. Although not assessed in our study, peri­ operative IL‑1 inhibition could provide other ben­ efits: it could reduce the incidence of postsurgical thrombosis or CNS dysfunction. The increased incidence of venous thrombosis after surgery is partly caused by hypercoagulability caused by a localized increase in tissue factor, which activates the coagulation cascade (reviewed in [21]). Tissue factor expression on the leukocyte and endothe­ lial cell surface is induced by many inflammatory mediators (e.g., IL‑1, ‑6 and ‑8, and TNF‑a; reviewed in [21,22]), whose activity or production were decreased by IL‑1 blockade in our murine studies [12] . IL‑1ra administration reduced pain in a rat model of a complex regional pain syn­ drome, which can develop after immobilization caused by fracture [23] . It has also been proposed that a hippocampal inflammatory response, which is associated with cytokine-dependent glial cell activation, may contribute to the post­ operative impairment of cognitive function [24] . Other in vitro [25] and in vivo [26] experimental data indicate that IL‑1ra administration attenu­ ates neuronal injury, ameliorates microglial acti­ vation after brain injury and reduces cognitive dysfunction after septic shock [27] . The big picture We currently treat postoperative pain with local anesthetics, to reduce the propagation of action potentials, or opioids, to reduce nociceptive signal transmission within the CNS. However, these measures do not attack the primary pro­ blem, which is the inflammation caused by the surgical incision. We have not clinically applied our extensive knowledge of the mediators of acute inflammation to alter the response within an injured tissue, to reduce local edema and pain, or promote wound healing. Perioperative

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Immunomodulation in perioperative medicine  administration of an IL‑1 inhibitor would repre­ sent an important step towards developing this approach. Toward this end, we are now perform­ ing a double-blind study to prospectively test the effect of perioperative IL‑1ra administration on incisional pain and on wound inflammatory mediator production. The therapy is adminis­ tered 1 h prior to incision and is continued for 24 h after the surgery. There could be a slight delay in analgesic onset, because the inflam­ matory mediators released immediately after incisional wounding may be arachadonic acid and/or reactive oxygen species [28] , or mitochon­ drial peptides or DNA [29] , which are not affected by IL‑1 inhibition. If this agent shows promise in the initial study, we hope to subsequently deter­ mine, in larger studies, if other postoperative complications, such as hypercoagulability, can be reduced. If perioperative IL‑1 inhibition does improve surgical outcome, this could dramatically alter our approach to postoperative pain management as there are many different immunomodulatory strategies that could also be utilized. The IL‑1 pathway is also blocked through inhibition of caspase‑1, a protease that converts pro-IL‑1b to the active cytokine, and small-molecule caspase‑1 inhibitors are under development for Bibliography 1

Gurtner GC, Werner S, Barrandon Y, Longaker MT: Wound repair and regeneration. Nature 453(7193), 314–321 (2008).

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Kehlet H, Holte K: Effect of postoperative analgesia on surgical outcome. Br. J. Anaesth. 87(1), 62–72 (2001).

3

Roy S, Khanna S, Rink C, Biswas S, Sen CK: Characterization of the acute temporal changes in excisional murine cutaneous wound inflammation by screening of the wound-edge transcriptome. Physiol. Genomics 34(2), 162–184 (2008).

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Martin P, Leibovich SJ: Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15(11), 599–607 (2005). Egozi EI, Ferreira AM, Burns AL, Gamelli RL, Dipietro LA: Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Repair Regen. 11(1), 46–54 (2003). Martin P, D’souza D, Martin J et al.: Wound healing in the PU.1 null mouse – tissue repair is not dependent on inflammatory cells. Curr. Biol. 13(13), 1122–1128 (2003).

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the control of inflammation in a variety of dis­ eases [30] . Additional antibody-based biologics that directly bind to IL‑1b are being developed. Other inflammatory mediators could also be targeted for controlling postincisional pain, edema or scaring. IL‑6, granulocyte colonystimulating factor, keratinocyte-derived chemo­ kine, MIP‑1a, TNF‑a and complement frag­ ment C5a are all increased within the wounded area after an incision. Inhibition of any of these mediators could reduce pain and improve wound healing. Overall, it is possible that surgical outcomes could be improved by perioperative immunomodulation, and this could become a standard part of pain management for surgeries performed in the 21st century. Financial & competing interests disclosure G Peltz was partially supported by a transformative RO1 award (1 R01 DK090992–01) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; part of the NIH). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Low QE, Drugea IA, Duffner LA et al.: Wound healing in MIP-1a-/- and MCP‑1-/mice. Am. J. Pathol. 159(2), 457–463 (2001).

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Devalaraja RM, Nanney LB, Du J et al.: Delayed wound healing in CXCR2 knockout mice. J. Invest. Dermatol. 115(2), 234–244 (2000).

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Dipietro LA, Reintjes MG, Low QE, Levi B, Gamelli RL: Modulation of macrophage recruitment into wounds by monocyte chemoattractant protein‑1. Wound Repair Regen. 9(1), 28–33 (2001).

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Hu Y, Liang D, Li X et al.: The role of interleukin‑1 in wound biology. Part I: murine in silico and in vitro experimental analysis. Anesth. Analg. 111(6), 1525–1533 (2010). Zheng M, Shafer SS, Liao G, Liu H-H, Peltz G: Computational genetic mapping in mice: ‘The Ship has Sailed’. Sci. Transl. Med. 1(3), 3ps4 (2009).

12 Hu Y, Liang D, Li X et al.: The role of

interleukin‑1 in wound biology. Part II: in vivo and human translational studies. Anesth. Analg. 111(6), 1534–1542 (2010).

13 Mertens M, Singh JA: Anakinra for

rheumatoid arthritis: a systematic review. J. Rheumatol. 36(6), 1118–1125 (2009). 14

Fleischmann RM, Tesser J, Schiff MH et al.: Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann. Rheum. Dis. 65(8), 1006–1012 (2006).

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Yang BB, Baughman S, Sullivan JT: Pharmacokinetics of anakinra in subjects with different levels of renal function. Clin. Pharmacol. Ther. 74(1), 85–94 (2003).

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Thomay AA, Daley JM, Sabo E et al.: Disruption of interleukin‑1 signaling improves the quality of wound healing. Am. J. Pathol. 174(6), 2129–2136 (2009).

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Ishida Y, Kondo T, Kimura A, Matsushima K, Mukaida N: Absence of IL‑1 receptor antagonist impaired wound healing along with aberrant NF‑kB activation and a reciprocal suppression of TGF‑b signal pathway. J. Immunol. 176(9), 5598–5606 (2006).

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Zhang X, Kohli M, Zhou Q, Graves DT, Amar S: Short- and long-term effects of IL‑1 and TNF antagonists on periodontal wound healing. J. Immunol. 173(5), 3514–3523 (2004).

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Editorial  Peltz 19

Wilusz RE, Weinberg JB, Guilak F, Mcnulty AL: Inhibition of integrative repair of the meniscus following acute exposure to interleukin‑1 in vitro. J. Orthop. Res. 26(4), 504–512 (2008).

20 Genovese MC, Cohen S, Moreland L et al.:

Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50(5), 1412–1419 (2004). 21

Martinelli I, Bucciarelli P, Mannucci PM: Thrombotic risk factors: basic pathophysiology. Crit. Care Med. 38(2 Suppl.), S3–S9 (2010).

22 Mackman N: Role of tissue factor in

hemostasis, thrombosis, and vascular development. Arterioscler. Thromb. Vasc. Biol. 24(6), 1015–1022 (2004). 23 Li WW, Guo TZ, Liang D et al.: The NALP1

inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. Pain 147(1–3), 277–286 (2009).

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24 Newman S, Stygall J, Hirani S, Shaefi S,

Maze M: Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology 106(3), 572–590 (2007). 25 Hailer NP, Vogt C, Korf HW, Dehghani F:

Interleukin‑1b exacerbates and interleukin‑1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures. Eur. J. Neurosci. 21(9), 2347–2360 (2005). 26 Sanderson KL, Raghupathi R, Saatman KE,

Martin D, Miller G, Mcintosh TK: Interleukin‑1 receptor antagonist attenuates regional neuronal cell death and cognitive dysfunction after experimental brain injury. J. Cereb. Blood Flow Metab. 19(10), 1118–1125 (1999). 27 Terrando N, Rei Fidalgo A, Vizcaychipi MP

et al.: The impact of IL‑1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit. Care 14(3), R88 (2010).

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28 Niethammer P, Grabher C, Look AT,

Mitchison TJ: A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459(7249), 996–999 (2009). 29 Zhang Q, Itagaki K, Hauser CJ:

Mitochondrial DNA is released by shock and activates neutrophils via p38 MAP-kinase. Shock 34(1), 55–59 (2010). 30 Wannamaker W, Davies R, Namchuk M

et al.: (S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethylbutanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydrofuran‑3‑yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase‑1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL‑1b and IL‑18. J. Pharmacol. Exp. Ther. 321(2), 509–516 (2007).

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