Ketamine Improves Sepsis-induced Immunosuppression by Attenuating Intracellular Calcium Elevation in Rat Peripheral Mononuclear Cells

Puspita Abidatul Qodariyah, Afiyf Kaysa Waafi, Christian Julio Suhardi, Karina Survival Rofiq, Aswoco Andyk Asmoro, Edi Widjajanto

Abstract


Immune response in sepsis divided into two phases, hyper-inflammation (cytokine storm) and hypo-inflammation (immunosuppression). The mechanism of immunosuppression appears to involve apoptosis of immune cells, particularly mononuclear cells and it predisposes to secondary infection that is believed as the predominant driving force for mortality. We aimed to determine the effect of ketamine  on mononuclear cells count related to intracellular calcium contained within these cells during the immunosuppression phase of sepsis.

This in vivo study was performed in Rattus Novergicus with Fecal Induced Perionitis (FIP) procedure to induce polymicrobial sepsis. Rats were treated with each respective dose of ketamine (2.5, 5, and 10 mg/kg) 1 hour after sepsis induction. Murine Sepsis Score was measured at 1 and 24 hours post-FIP. After 24 hours, animals were sacrificed, and the percentage of intracellular calcium inside CD4, and CD8 T cells, B cells and monocytes, along with these cells counts were determined with flowcytometry.  

There are significant elevation of intracellular calcium in CD4 T-cells, B-cells and monocytes after FIP-induction and ketamine treatment suppressed this FIP-induced elevation. Measurement of mononuclear cells count showed a relevant result, in which FIP induced mononuclear cells massive loss and ketamine could inhibit the loss. MSS data showed ketamine 5 mg/kg could improve 24 hours MSS with 100% survivability.

These findings suggest that ketamine have an inhibitory effect in mononuclear-cells apoptosis mechanism through attenuating intracellular calcium elevation in polymicrobial sepsis. These inhibitory effects of ketamine might correlate with a better survival and clinical outcome.


Keywords


Sepsis; ketamine; immunosuppression; mononuclear cells; intracellular calcium

Full Text:

PDF

References


A. Zeiler, F. (2015). NMDA Receptor Antagonism in Refractory Status Epilepticus: Right Idea, Wrong Target? Brain Disorders & Therapy, 4(5). http://doi.org/10.4172/2168-975X.1000195

Asmoro, A. A., Rakhmatullah, R., Puspitasari, S., Tarimah, K., Saleh, S. C., Widodo, M. A., & Widjajanto, E. (2015). The effect of ketamine on the lipopolysaccharide-induced inflammation in in vitro culture of HUVEC. Asian Pacific Journal of Tropical Disease, 5(11), 894–896. http://doi.org/10.1016/S2222-1808(15)60952-5

Ayala, A., Perl, M., Venet, F., Lomas-Neira, J., Swan, R., & Chung, C. S. (2008). Apoptosis in sepsis: mechanisms, clinical impact and potential therapeutic targets. Current Pharmaceutical Design, 14(19), 1853–1859. http://doi.org/10.2174/138161208784980617

Boomer, J. S., Green, J. M., & Hotchkiss, R. S. (2014). The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence, 5(1), 45–56. http://doi.org/10.4161/viru.26516

Condotta, S. A., Rai, D., James, B. R., Griffith, T. S., & Badovinac, V. P. (2013). Sustained and incomplete recovery of naive CD8+ T cell precursors after sepsis contributes to impaired CD8+ T cell responses to infection. Journal of Immunology (Baltimore, Md. : 1950), 190(5), 1991–2000. http://doi.org/10.4049/jimmunol.1202379

de Pablo, R., Monserrat, J., Prieto, A., & Alvarez-Mon, M. (2014). Role of circulating lymphocytes in patients with sepsis. BioMed Research International, 2014, 671087. http://doi.org/10.1155/2014/671087

Dellinger, R. P., Levy, M. M., Rhodes, A., Annane, D., Gerlach, H., Opal, S. M., … Subgroup*, T. S. S. C. G. C. including T. P. (2013). Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Medicine, 39(2), 165–228. http://doi.org/10.1007/s00134-012-2769-8

Eibl, M., & Mannhalter, J. W. (1982). Macrophage-lymphocyte interaction in response to a bacterial antigen ( E . coli ), 260–268.

Feske, S. (2007). Calcium signalling in lymphocyte activation and disease. Nature Reviews Immunology, 7(9), 690–702. http://doi.org/10.1038/nri2152

Hotchkiss, R. S., Monneret, G., & Payen, D. (2013a). Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews. Immunology, 13(12), 862–74. http://doi.org/10.1038/nri3552

Hotchkiss, R. S., Monneret, G., & Payen, D. (2013b, March). Immunosuppression in sepsis: A novel understanding of the disorder and a new therapeutic approach. The Lancet Infectious Diseases. NIH Public Access. http://doi.org/10.1016/S1473-3099(13)70001-X

Lang, J. D., & Matute-Bello, G. (2009). Lymphocytes, apoptosis and sepsis: making the jump from mice to humans. Critical Care (London, England), 13(1), 109. http://doi.org/10.1186/cc7144

Lauvau, G., & Goriely, S. (2016). Memory CD8+ T Cells: Orchestrators and Key Players of Innate Immunity? PLOS Pathogens, 12(9), e1005722. http://doi.org/10.1371/journal.ppat.1005722

Loix, S., Hospitalier, C., & Chwapi, M. D. K. (2011). The anti-inflammatory effects of ketamine : State of the art. Acta Anaesthesiologica Belgica, 62, 47–58.

Luckheeram, R. V., Zhou, R., Verma, A. D., & Xia, B. (2012). CD4 + T Cells : Differentiation and Functions, 2012. http://doi.org/10.1155/2012/925135

Monserrat, J., de Pablo, R., Diaz-Martín, D., Rodríguez-Zapata, M., de la Hera, A., Prieto, A., & Alvarez-Mon, M. (2013). Early alterations of B cells in patients with septic shock. Critical Care (London, England), 17(3), R105. http://doi.org/10.1186/cc12750

Mortadza, S. A. S., Wang, L., Li, D., & Jiang, L.-H. (2015). TRPM2 Channel-Mediated ROS-Sensitive Ca(2+) Signaling Mechanisms in Immune Cells. Frontiers in Immunology, 6(August), 407. http://doi.org/10.3389/fimmu.2015.00407

Parenti, A., De Logu, F., Geppetti, P., & Benemei, S. (2016). What is the evidence for the role of TRP channels in inflammatory and immune cells? British Journal of Pharmacology, 173(6), 953–969. http://doi.org/10.1111/bph.13392

Review, M. (2010). Monocyte development , characterization and role in disease Mini Review, 1–8.

Ru, X., & Yao, X. (2014). TRPM2: a multifunctional ion channel for oxidative stress sensing. Sheng Li Xue Bao : [Acta Physiologica Sinica], 66(1), 7–15. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24553864

Schepers, E., Glorieux, G., Dhondt, A., Leybaert, L., & Vanholder, R. (2009). Flow cytometric calcium flux assay: evaluation of cytoplasmic calcium kinetics in whole blood leukocytes. Journal of Immunological Methods, 348(1–2), 74–82. http://doi.org/10.1016/j.jim.2009.07.002

Shrum, B., Anantha, R. V, Xu, S. X., Donnelly, M., Haeryfar, S., McCormick, J. K., & Mele, T. (2014). A robust scoring system to evaluate sepsis severity in an animal model. BMC Research Notes, 7(1), 233. http://doi.org/10.1186/1756-0500-7-233

Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., … Angus, D. C. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8), 801. http://doi.org/10.1001/jama.2016.0287

Sun, J., Zhou, Z. Q., Lv, R., Li, W. Y., & Xu, J. G. (2004). Ketamine inhibits LPS-induced calcium elevation and NF-kappa B activation in monocytes. Inflammation Research, 53(7). http://doi.org/10.1007/s00011-004-1262-4

Sundar, K. M., & Sires, M. (2013). Sepsis induced immunosuppression: Implications for secondary infections and complications. Indian Journal of Critical Care Medicine : Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine, 17(3), 162–9. http://doi.org/10.4103/0972-5229.117054

Taniguchi, T., Kanakura, H., Takemoto, Y., Kidani, Y., & Yamamoto, K. (2003). Effects of ketamine and propofol on the ratio of interleukin-6 to interleukin-10 during endotoxemia in rats. The Tohoku Journal of Experimental Medicine, 200(2), 85–92.

Unsinger, J., McDonough, J. S., Shultz, L. D., Ferguson, T. A., & Hotchkiss, R. S. (2009). Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice. Journal of Leukocyte Biology, 86(2), 219–227. http://doi.org/10.1189/jlb.1008615

Walton, A. H., Muenzer, J. T., Rasche, D., Boomer, J. S., Sato, B., Brownstein, B. H., … Hotchkiss, R. S. (2014). Reactivation of Multiple Viruses in Patients with Sepsis. PLoS ONE, 9(6), e98819. http://doi.org/10.1371/journal.pone.0098819

Xie, Y. F., MacDonald, J. F., & Jackson, M. F. (2010). TRPM2, calcium and neurodegenerative diseases. International Journal of Physiology, Pathophysiology and Pharmacology, 2(2), 95–103.




DOI: https://doi.org/10.21776/ub.rjls.2018.005.01.1

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.