Immunopathogenesis and immunotherapy in the control of the infectious process of gunshot wounds
https://doi.org/10.24884/1607-4181-2026-33-1-30-39
Abstract
Infectious complications develop in 82.5% of patients with a gunshot wound, which is one of the main causes of mortality. The increased susceptibility of patients with gunshot wounds to infections is due to the suppressed state of the immune system that develops after injury. Immunological disorders are the consequences of trauma and pose a serious problem in the combined treatment of infectious complications. The general immune response to multiple trauma is a multilevel complex of neurohormonal, cellular, and hemodynamic factors that first lead to excessive activation of the immune system, and then, due to its depletion, to immunosuppression, up to immunoparalysis. Immunoparalysis is characterized by a decrease in the ability of antigen-presenting cells (macrophages and dendritic cells) to perform an antigen-presenting function, providing an adequate response to pathogens and a sharp decrease in T-cells, primarily T helper cells, which regulate the cellular link of immunity. Activation of immunocompetent and functionally related cells in response to trauma leads to hyperproduction of endogenous pro-inflammatory bioregulators, which play a leading role in the development of systemic inflammatory reactions, organ and multiple organ failure. Hyperactivation of the immune system ultimately leads to depletion of secretory activity and death of immunocompetent cells, contributing to the development of immunosuppression. Immune depression is the direct cause of a decrease in the body defenses and the addition of infections caused by opportunistic, usually antibiotic-resistant microorganisms. Thus, the preservation and restoration of immune function is an important strategy, which, along with countering the excessive production of inflammatory mediators, can significantly improve the treatment outcomes of patients with gunshot wounds.
About the Authors
M. V. Kiselevskii
N. N. Blokhin National Medical Research Center of Oncology
Russian Federation
Competing Interests:
Russian Federation
Kiselevskii Mikhail V., Dr. of Sci. (Med.), Professor, Head of the Laboratory of Cellular Immunity
24, Kashirskoe shosse, Moscow, 115522
Competing Interests:
Author declares no conflict of interest.
S. Ia. Ivanusa
Military Medical Academy
Russian Federation
Competing Interests:
Russian Federation
Ivanusa Sergei Ia., Dr. of Sci. (Med.), Professor, Colonel of the Medical Service, Head of the Department of General Surgery
6, Academica Lebedeva str., Saint Petersburg, 194044
Competing Interests:
Author declares no conflict of interest.
M. V. lazutkin
Military Medical Academy
Russian Federation
Competing Interests:
Russian Federation
Lazutkin Maksim V., Dr. of Sci. (Med.), Professor, Colonel of the Medical Service, Deputy Head of the Department of General Surgery
6, Academica Lebedeva str., Saint Petersburg, 194044
Competing Interests:
Author declares no conflict of interest.
S. G. Dragunov
Military Medical Academy
Russian Federation
Competing Interests:
Russian Federation
Dragunov Sergei G., Major of the Medical Service, Associate Professor of the Department of General Surgery
6, Academica Lebedeva str., Saint Petersburg, 194044
Competing Interests:
Author declares no conflict of interest.
E. I. Petrova
Military Medical Academy
Russian Federation
Competing Interests:
Russian Federation
Petrova Ekaterina I., Clinical Resident of the Department of General Surgery
6, Academica Lebedeva str., Saint Petersburg, 194044
Competing Interests:
Author declares no conflict of interest.
References
1. Billiar T. R., Vodovotz Y. Time for trauma immunology // PLoS Med. 2017;14:e1002342. https://doi.org/10.1371/journal.pmed.1002342.
2. Netea M. G., Balkwill F., Chonchol M. et al. A guiding map for inflammation // Nat. Immunol. 2017;18:826–831. https://doi.org/10.1038/ni.3790.
3. Gentile L. F., Moldawer L. L. DAMPs, PAMPs, and the origins of SIRS in bacterial sepsis // Shock. 2013;39:113–114. https://doi.org/10.1097/SHK.0b013e318277109c.
4. McDonald B., Pittman K., Menezes G. B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation // Science. 2010;330:362–366.
5. Aneja R., Odoms K., Dunsmore K. et al. Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells // J. Immunol. 2006;177:7184–7192. https://doi.org/10.4049/jimmunol.177.10.7184.
6. Zhao H., Kilgas S., Alam A. et al. The role of extracellular adenosine triphosphate in ischemic organ injury // Crit. Care Med. 2016;44(5):1000–1012. https://doi.org/10.1097/CCM.0000000000001603.
7. Gebhard F., Huber-Lang M. Polytrauma–pathophysiology and management principles // Langenbecks Arch. Surg. 2008;393:825–883.
8. Zhang Q., Raoof M., Chen Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury // Nature. 2010;464:104–107. https://doi.org/10.1038/nature08780.
9. Davis G. E., Bayless K. J., Davis M. J. et al. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules // Am. J. Pathol. 2000;156(5):1489–1498. https://doi.org/10.1016/S0002-9440(10)65020-1.
10. Cabrera C. P., Manson J., Shepherd J. M. et al. Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study // PLoS Med. 2017;14(7):e1002352. https://doi.org/10.1371/journal.pmed.1002352.
11. Cekic C., Linden J. Purinergic regulation of the immune system // Nat. Rev. Immunol. 2016;16(3):177–92. https://doi.org/10.1038/nri.2016.4.
12. Xiao W., Mindrinos M. N., Seok J. et al. A genomic storm in critically injured humans // J. Exp. Med. 2011;208:2581–2590. https://doi.org/10.1084/jem.20111354.
13. Lederer J. A., Brownstein B. H., Lopez M. C. et al. Comparison of longitudinal leukocyte gene expression after burn injury or trauma-hemorrhage in mice // Physiol. Genomics. 2008;32(3):299–310. https://doi.org/10.1152/physiolgenomics.00086.2007.
14. Seshadri A., Brat G. A., Yorkgitis B. K. et al. Phenotyping the immune response to trauma: a multiparametric systems immunology approach // Crit. Care Med. 2017;45(9):1523– 1530. https://doi.org/10.1097/CCM.0000000000002577.
15. Matijevic N., Wang Y. W., Holcomb J. B. et al. Microvesicle phenotypes are associated with transfusion requirements and mortality in subjects with severe injuries // J. Extracell. Vesicles. 2015;4:29338. https://doi.org/10.3402/jev.v4.29338.
16. Timmermans K., Kox M., Vaneker M. et al. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients // Intensive Care Med. 2016;42(4):551–561. https://doi.org/10.1007/s00134-015-4205-3.
17. Jones H. R., Robb C. T., Perretti M. et al. The role of neutrophils in inflammation resolution // Semin. Immunol. 2016;28(2):137–145. https://doi.org/10.1016/j.smim.2016.03.007.
18. Keel M., Trentz O. Pathophysiology of polytrauma // Injury. 2022;53(7):2400–2412. https://doi.org/10.1016/j.injury.2022.04.009.
19. Burk A. M., Martin M., Flierl M. A. et al. Early complementopathy after multiple injuries in humans // Shock. 2012;37:348–354. https://doi.org/10.1097/SHK.0b013e3182471795.
20. Frith D., Goslings J. C., Gaarder C. et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations // J. Thromb. Haemost. 2010;8(9):1919– 1925. https://doi.org/10.1111/j.1538-7836.2010.03945.x.
21. Hazeldine J., Naumann D. N., Toman E. et al. Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study // PLoS Med. 2017;14(7):e1002338. https://doi.org/10.1371/journal.pmed.1002338.
22. Chen W., Sheng J., Guo J. et al. Cytokine cascades induced by mechanical trauma injury alter voltage-gated sodium channel activity in intact cortical neurons // J. Neuroinflammation. 2017;14(1):73. https://doi.org/10.1186/s12974-017-0847-0.
23. Paunel-Görgülü A., Kirichevska T., Lögters T. et al. Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis // Mol. Med. 2012;18(1):325–35. https://doi.org/10.2119/molmed.2011.00380.
24. Kottke M. A., Walters T. J. Where’s the leak in vascular barriers? A review // Shock. 2016;46:20–36.
25. Gentile L. F., Cuenca A. G., Efron P.A. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care // J. Trauma Acute Care Surg. 2012;72(6):1491–501. https://doi.org/10.1097/TA.0b013e318256e000.
26. Bandyopadhyay G., De A., Laudanski K. et al. Negative signalling contributes to T-cell anergy in trauma patients // Critical Care Medicine. 2007;35:794–801. https://doi.org/10.1097/01.CCM.0000256847.61085.A5.
27. Venet F., Chung C. S., Kherouf H. et al. Increased circulating regulatory T cells (CD4(+)CD25(+)CD127(-)) contribute to lymphocyte anergy in septic shock patients // Intensive Care Medicine. 2009;35:678–686. https://doi.org/10.1007/s00134-008-1337-8.
28. Cheadle W. G., Pemberton R. M., Robinson D. et al. Lymphocyte subset responses to trauma and sepsis // Journal of Trauma. 1993;35:844–849. https://doi.org/10.1097/00005373-199312000-00007.
29. Yamada R., Tsuchida S., Hara Y. et al. Apoptotic lymphocytes induced by surgical trauma in dogs // Journal of Anesthesia. 2002;16:131–137. https://doi.org/10.1007/s005400200008.
30. Zahorec R. Ratio of neutrophil to lymphocyte counts - rapid and simple parameter of systemic inflammation and stress in critically ill // Bratislavské lekárske listy. 2001;102:5–14.
31. Menges T., Engel J., Welters I. et al. Changes in blood lymphocyte populations after multiple trauma: association with post-traumatic complications // Critical Care Medicine. 1999;27:733–740. https://doi.org/10.1097/00003246-199904000-00026.
32. Puyana J., Pellegrini J. D., De A. K. et al. Both T-helper1 and T-helper2 type lymphokines are depressed in posttrauma anergy // Journal of Trauma. 1998;44:1037–1045. https://doi.org/10.1097/00005373-199806000-00017.
33. Kiselevskiy M., Shubina I., Chikileva I. et al. Immune Pathogenesis of COVID-19 Intoxication: Storm or Silence? // Pharmaceuticals (Basel). 2020;13(8):166. https://doi.org/10.3390/ph13080166.
34. Venet F., Bohé J., Debard A. L. et al. Both percentage of gamma-delta T lymphocytes and CD3 expression are reduced during septic shock // Critical Care Medicine. 2005;33:2836– 2840. https://doi.org/10.1097/01.CCM.0000189745.66585.AE.
35. Kiselevsky M. V., Sitdikova S. M., Abdullaev A. G. et al. Immunosuppression in sepsis and the possibility of its correction // Grekov’s Bulletin of Surgery. 2018;177(5):105–107. (In Russ.).
36. Heffernan D. S., Monaghan S. F., Thakkar R. K. et.al Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern // Crit Care. 2012;16(1):R12. https://doi.org/10.1186/cc11157.
37. Lord J. M., Midwinter M. J., Chen Y. F. et al. The systemic immune response to trauma: an overview of pathophysiology and treatment // Lancet. 2014;384(9952):1455–1465. https://doi.org/10.1016/S0140-6736(14)60687-5.
38. Kaukonen K. M., Bailey M., Pilcher D. et al. Systemic inflammatory response syndrome criteria in defining severe sepsis // N. Engl. J. Med. 2015;372(17):1629–1638. 10.1056/NEJMoa1415236.
39. Ward N. S., Casserly B., Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients // Clin. Chest. Med. 2008;29(4):617–625. 10.1016/j.ccm.2008.06.010.
40. Adib-Conquy M., Cavaillon J. M. Compensatory anti-inflammatory response syndrome // Thromb Haemost. 2009;101(1):36–47.
41. Xiao W., Mindrinos M. N., Seok J. et al. A genomic storm in critically injured humans // J. Exp. Med. 2011;208(13):2581–2590. 10.1084/jem.2011135.
42. Kruglova T. S., Fomina D. S., Poteshkina N. G. et al. Criteria for the optimal use of interleukin-6 receptor blockers in patients withCOVID-19 // Ter. Arkh. 2021;93(11):1316– 1324. (In Russ.). https://doi.org/10.26442/00403660.2021.11.201248.
43. Muravyeva N. V., Belov B. S. Interleukin-6 inhibitors: from the therapy of immuno-inflammatory rheumatic diseases to use in COVID-19 // Meditsinskiy Sovet. 2022;16(11):88–94. (In Russ.). https://doi.org/10.21518/2079-701X-2022-16-11-88-94.
44. Hamilton F. W., Thomas M., Arnold D. et al. Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study // PLoS Med. 202320(1):e1004174. https://doi.org/10.1371/journal.pmed.1004174.
45. Grumet M., Sherman J., Dorf B. S. Efficacy of MSC in Patients with Severe COVID-19: Analysis of the Literature and a Case Study // Stem. Cells Transl. Med. 2022;11(11):1103– 1112. https://doi.org/10.1093/stcltm/szac067.
46. Kiselevsky M. V., Gromova E. G., Fomin A. M. Sepsis. Etiology. Pathogenesis. Extracorporeal detoxification. Practical medicine. 2021; 170 p. (In Russ.).
47. Francois B., Jeannet R., Daix T. et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial // JCI Insight. 2018;3(5):e98960. https://doi.org/10.1172/jci.insight.98960.
48. Daix T., Mathonnet A., Brakenridge S. et al. Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial //Ann. Intensive Care. 2023;13(1):17. https://doi.org/10.1186/s13613-023-01109-w.
49. Shi H., Wang W., Yin J. et al. The inhibition of IL-2/ IL-2R gives rise to CD8+ T cell and lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia // Cell Death Dis. 2020;11(6):429. https://doi.org/10.1038/s41419-020-2636-4.
50. Mahmoudpour S. H., Jankowski M., Valerio L. et al. Safety of low-dose subcutaneous recombinant interleukin-2: Systematic review and meta-analysis of randomized controlled trials. Sci. Rep. 2019;9(1):7145. https://doi.org/10.1038/s41598-019-43530-x.
51. Crespo M., Caragol I., Falcó V. et al. Efficacy of recombinant interleukin-2 (rIL-2) in patients with advanced HIV-1 infection and blunted immune response to HAART // Enferm Infecc Microbiol Clin. 2008;26:27–31. https://doi.org/10.1157/13114392.
52. Overwijk W. W., Tagliaferri M. A., Zalevsky J. Engineering IL-2 to give new life to T cell immunotherapy // Annu. Rev. Med. 2021;72:281–311. https://doi.org/10.1146/annurev-med-073118-011031.
53. Schub D., Klemis V., Schneitler S. et al. High levels of SARS-CoV-2-specific T cells with restricted functionality in severe courses of COVID-19 // JCI Insight. 2020;5(20):e142167. https://doi.org/10.1172/jci.insight.142167.
54. Zhu M. E., Wang Q., Zhou S. et al. Recombinant interleukin-2 stimulates lymphocyte recovery in patients with severe COVID-19 // Exp. Ther. Med. 2021;21(3):227. https://doi.org/10.3892/etm.2021.9658.
55. Anisimov A. Yu. Immunotherapy with Roncoleukin in the Complex Treatment of Patients with Abdominal Sepsis // Russian J. Immunol. 2004;9(suppl.1):234. (In Russ.).
56. Lebedev V. F., Gavrilin S. V., Kozlov V. K. Immunoprophylaxis and advanced therapy of post-traumatic sepsis with yeast recombinant interleukin-2 // Cytokines and Inflammation. 2002;1:46–47. (In Russ.).
57. Lebedev M. F., Gavrilin S. V., Kozlov V. K. et al. Experience of using Roncoleukin in the early period of traumatic disease // Terra Medica. 2001;3:35–37. (In Russ.).
58. Gavrilin S. V., Kozlov V. K., Lebedev V. F. Immunopathogenesis of severe wounds and injuries: possibilities of immunocorrection // Grekov’s Bulletin of Surgery. 2002;4:85–90. (In Russ.).
59. Patera A. C., Drewry A. M., Chang K. et al. Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1 // J. Leukoc. Biol. 2016;100:1239–125.
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Kiselevskii M.V., Ivanusa S.I., lazutkin M.V., Dragunov S.G., Petrova E.I. Immunopathogenesis and immunotherapy in the control of the infectious process of gunshot wounds. The Scientific Notes of the Pavlov University. 2026;33(1):30-39. (In Russ.) https://doi.org/10.24884/1607-4181-2026-33-1-30-39
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