The dynamics of oxidoreductase expression in the liver during experimental peritonitis and the role of p38 MAPK inhibition

Background. Oxidative stress is crucial in the pathogenesis of endogenous intoxication syndrome in acute surgical abdominal pathology. The enzyme systems of oxidative phosphorylation and cytochrome reductase are vital for hepatocyte energy potential. This study aimed to investigate the effects of a p38 MAPK inhibitor on cytochrome b5 reductase 3 (CYB5R3); cytochrome c oxidase; and microsomal oxidation in experimental peritonitis.

Methods. A model of peritonitis was used with two groups: a control group without treatment (n = 15) and a main group treated with adezmapimod conjugate on endof-surgery (n = 15). Immunomorphological staining was employed to evaluate CYB5R3 and cytochrome oxidase expression on days 3; 7; and 14. The intensity of staining was scored from 0 to 4; and differences were assessed using multiple comparison tests and the Mann-Whitney criterion.

Results. In the control group; CYB5R3 intensity decreased from 2.5 [2.0;3.0] on day 3 to 1.0 [1.0;1.0] on day 14. Conversely; in the main group; the inhibitor maintained high enzyme expression throughout the study. On day 3; cytochrome oxidase levels differed significantly between groups: 1.0 [1.0;2.0] in the control and 4.0 [3.0;4.0] in the main group (p < 0.05).

Conclusion. The findings suggest that adezmapimod conjugate positively affects the integrity of enzyme systems; maintaining redox balance and oxidative phosphorylation in hepatocytes during peritonitis.

1. Sazhin VP, Каrsаnоv АN, Маsкin SS, Rемizоv ОV. What is sepsis: 25 years of experience in concept development. Hirurgiya. Zhurnal im. N.I. Pirogova. 2017; 1: 82-87. (In Russ.). doi: 10.17116/hirurgia2017182-87

2. Vlаsоv АP, Bolotskih VА, Shejranov NS, Bolushev PО, Glushkov VМ, Gаninа МV, et al. Oxidative stress and phospholipase activation are factors in the progression of endogenous intoxication. Sovremennye problemy nauki i obrazovaniya. 2019; 4: 3. (In Russ.).

3. McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr. Biol. 2006; 16(14): R551-R560. doi: 10.1016/j.cub.2006.06.054

4. Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Sig. Transduct. Target Ther. 2023; 8(1): 333. doi: 10.1038/s41392-023-01547-9

5. Vercellino I, Sazanov LA. The assembly, regulation and function of the mitochondrial respiratory chain. Nat. Rev. Mol. Cell Biol. 2022; 23(2): 141–161. doi: 10.1038/s41580-021-00415-0

6. McClave SA, Wischmeyer PE, Miller KR, Zanten ARH. Mitochondrial Dysfunction in Critical Illness: Implications for Nutritional Therapy. Curr. Nutr. Rep. 2019; 8(4): 363–373. doi: 10.1007/s13668-019-00296-y

7. Supinski GS, Schroder EA, Callahan LA. Mitochondria and Critical Illness. Chest. 2020; 157(2): 310-322. doi: 10.1016/j.chest.2019.08.2182

8. Chepurnyh ЕЕ, Bogorodskaya SL, Shurygina IА, Rodionova LV, Samojlova LG, Shurygin MG. Dynamics of ATP-aze activity and indicators of lipid peroxidation in liver tissue in experimental peritonitis using the drug “Serogard”. Acta Biomedica Scientifica. 2024; 9(6): 228-238. (In Russ.). doi: 10.29413/ABS.2024-9.6.23

9. Hu D, Prabhakaran HS, Zhang YY, Luo G, He W, Liou Y-C. Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives. Crit. Care. 2024; 28: 292. doi: 10.1186/s13054-024-05069-w

10. Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. Mitochondrial proton and electron leaks. Essays Biochem. 2010; 47: 53-67. doi: 10.1042/bse0470053

11. Yang X, Lu GP, Cai XD, Lu ZJ, Kissoon N. Alterations of complex IV in the tissues of a septic mouse model. Mitochondrion. 2019; 49: 89-96. doi: 10.1016/j.mito.2018.11.008

12. Choumar A, Tarhuni A, Letteron P, Reyl-Desmars F, Dauhoo N, Damasse J, et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid. Redox Signal. 2011; 15(11): 2837-2854. doi: 10.1089/ars.2010.3713

13. Hall R, Yuan S, Wood K, Katona M, Straub AC. Cytochrome b5 reductases: Redox regulators of cell homeostasis. J. Biol. Chem. 2022; 298(12): 102654. doi: 10.1016/j.jbc.2022.102654

14. Elahian F, Sepehrizadeh Z, Moghimi B, Mirzaei SA. Human cytochrome b5 reductase: structure, function, and potential applications. Crit. Rev. Biotechnol. 2014; 34(2): 134-143. doi: 10.3109/07388551.2012.732031

15. Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR. p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell. 2007; 11(2): 191- 205. doi: 10.1016/j.ccr.2006.12.013

16. Keshari RS, Verma A, Barthwal MK, Dikshit M. Reactive oxygen species-induced activation of ERK and p38 MAPK mediates PMA-induced NETs release from human neutrophils. J. Cell Biochem. 2013; 114(3): 532-540. doi: 10.1002/jcb.24391

17. Chepurnyh ЕЕ, Shurygina IA, Fadeeva ТV, Dremina NN, Shurygin МG. The use of p38-MARK blockers in the treatment of experimental peritonitis. Klinicheskaya i eksperimental’naya hirurgiya. Zhurnal imeni akademika B.V. Petrovskogo. 2024; 12(3): 32-39. (In Russ.). doi: 10.33029/2308-1198-2024-12-3-32-39

18. Shurygin MG, Bogorodskaya SL, Chepurnykh EE, Rodionova LV, Samojlova LG, Shurygina IA. Assessment of proteolytic processes by the level of low molecular weight proteins in experimental peritonitis and under the conditions of using the drug “Serogard”. Vestnik Avicenny. 2024; 26(3): 417-426. (In Russ.). doi: 10.25005/2074-0581-2024-26-3-417-426

19. Fadeevа ТV, Shurygina IA, Dremina NN, Vetohina АV, Chepurnyh ЕЕ, Shurygin МG. Bacterial translocation in experimental peritonitis. Zabajkal’skij medicinskij vestnik. 2019; 4: 128-133. (In Russ.). doi: 10.52485/19986173_2019_4_128

20. Shurygina IA, Shurygin MG, Chepurnykh EE. Method for treating enteral insufficiency in inflammatory and traumatic injuries of the peritoneum: Patent No. 2749435 of the Russian Federation. 2021; (16). (In Russ.).

21. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002; 360(9328): 219-223. doi: 10.1016/S0140-6736(02)09459-X

22. Romodin LА. Cytochrome C complex with cardiolipin. Part 1. Cytochrome C and cardiolipin (literature review). Vestnik novyh medicinskih tekhnologij. 2021; 28(3): 64-67. (In Russ.). doi: 10.24412/1609-2163-2021-3-64-67

23. Yarockaya NN, Samsonova IV, Kosinec VА. The effect of metabolic drugs on the intensity of cytochrome C expression in experimental widespread purulent peritonitis. Novosti hirurgii. 2016; 24(1): 62-69. (In Russ.). doi: 10.18484/2305-0047.2016.1.62

24. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006; 12: 446–451. doi: 10.1038/nm1388