Volatile anesthetics are major drugs to provide general anesthesia during perioperative period. While the primary purpose is to provide analgesia, hypnosis and immobility, they are suggested to possess immunomodulatory effects. Alternation of immune function by volatile anesthetics can be clinically significant particularly fr critical-ill patients. Candidate's long-term goal is 1) to elucidate the molecular mechanism and degree of immunomodulatory effects by various, clinically-used anesthetics, thereby providing clinicians the rational to use one anesthetic over others in the context of patient's underlying diseases, and 2) to redesign new anesthetics without immunomodulation. We focused our target on two adhesion molecules L2 and M2 that are expressed exclusively on leukocytes, playing a role in leukocyte arrest on the endothelium, phagocytosis, immunological synapse formation, natural killer cells cytotoxicity, and so on. In our preliminary experiments, we showed that L2 and M2 are functionally inhibited by isoflurane. Also L2, not M2 was inhibited by sevoflurane. We hypothesize that volatile anesthetics bind to these integrins and modify their functions, thereby modulating immune function. In this proposal, we will investigate how volatile anesthetics interact with these molecules structurally. Our proposed research consists of three Aims, and will be performed in Immune Disease Institute (Program in Cellular and Molecular Medicine in Children's Hospital Boston).
In Aim1 and Aim 2, we will determine the interaction of clinically used anesthetics with L2 and M2 and their binding site(s). The effects of volatile anesthetics on ligand binding will be assessed in cell-free and cell-based assays using flow cytometery and V-bottom assay. The binding parameters will be measured with isothermal titration calorimetry. Anesthetic binding site(s) will be assessed in the combination of X ray crystallography and photoactivatable anesthetics.
In Aim3, we will examine biological effects by volatile anesthetics resulting from the impairment of these adhesion molecules'function. We will use natural killer cells cytotoxicity assay, Fc receptor mediated neutrophil cytotoxicity and phagocytosis assay for this purpose. Subsequently, our experimental results will provide insight into the underlying mechanism of volatile anesthetics-induced immunomodulation.

Public Health Relevance

Immunomodulation by volatile anesthetics has been described in literature, but there is lack of knowledge how, which and when anesthetics will cause immunomodulation. We propose to address the mechanism of volatile anesthetics-induced immunomodulation. Understanding the mechanism, the degree, and significance of these effects is important to formulate our daily practice of general anesthesia, and potentially impact on the outcomes of patients undergoing surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM101345-03
Application #
8636035
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Yuki, Koichi; Matsunami, Erika; Tazawa, Kazumasa et al. (2017) Pediatric Perioperative Stress Responses and Anesthesia. Transl Perioper Pain Med 2:1-12
Tazawa, Kazumasa; Koutsogiannaki, Sophia; Chamberlain, Matthew et al. (2017) The effect of different anesthetics on tumor cytotoxicity by natural killer cells. Toxicol Lett 266:23-31
Okuno, Toshiaki; Koutsogiannaki, Sophia; Ohba, Mai et al. (2017) Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production. FASEB J 31:1584-1594
Koutsogiannaki, Sophia; Schaefers, Matthew M; Okuno, Toshiaki et al. (2017) From the Cover: Prolonged Exposure to Volatile Anesthetic Isoflurane Worsens the Outcome of Polymicrobial Abdominal Sepsis. Toxicol Sci 156:402-411
Chamberlain, Matthew; Koutsogiannaki, Sophia; Schaefers, Matthew et al. (2017) The Differential Effects of Anesthetics on Bacterial Behaviors. PLoS One 12:e0170089
Yuki, Koichi; Eckenhoff, Roderic G (2016) Mechanisms of the Immunological Effects of Volatile Anesthetics: A Review. Anesth Analg 123:326-35
Greenwald, Emily; Yuki, Koichi (2016) A translational consideration of intercellular adhesion molecule-1 biology in the perioperative setting. Transl Perioper Pain Med 1:17-23
Jung, Sungeun; Yuki, Koichi (2016) Differential effects of volatile anesthetics on leukocyte integrin macrophage-1 antigen. J Immunotoxicol 13:148-56
Yuki, Koichi; Murakami, Naoka (2015) Sepsis pathophysiology and anesthetic consideration. Cardiovasc Hematol Disord Drug Targets 15:57-69
Bu, Weiming; Pereira, Luis M; Eckenhoff, Roderic G et al. (2014) Stereoselectivity of isoflurane in adhesion molecule leukocyte function-associated antigen-1. PLoS One 9:e96649

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