Effect of isoniazid and its compositions with oxidized dextran on the activity of inflammation and destruction processes in the liver of mice with BCG granulomatosis

Introduction. Tuberculosis is among the most common infectious diseases in humans. One of the main drugs for treating tuberculosis, isoniazid, has a wide range of adverse effects, including hepatotoxicity, making the search for ways to reduce its toxic reactions highly relevant.
The aim of the study was to assess liver damage, as well as the levels of the cytokines IL-6 and TNF-α, metalloproteinases MMP1 and MMP9, and the protease inhibitor TIMP-1 in mice with BCG granulomatosis. These factors were evaluated immunohistochemically following intraperitoneal injection of isoniazid, dextrazide, or a liposomal form of dextrazide (LFD), along with its inhalational injection.
Methods. Fifty male BALB/c mice were infected with BCG vaccine via retroorbital route. After 3 months, isoniazid or its compositions with oxidized dextran were injection twice a week at a dose of 14 mg/kg body weight for 2 months; the control group received NaCl solution. Liver was followed by histological processing and immunohistochemistry.
Results. Tuberculosis granulomas were detected in the liver 5 months after infection. The total number of granulomas was reduced in mice receiving all forms of isoniazid, but LFD injection by inhalation was the most effective. The volume densities of lymphoid infiltrates and tissue damage were greatest in the livers of mice injected with NaCl, with lower values observed in the isoniazid-treated groups. The number of cells producing IL-6, MMP1, and MMP9 was highest in the isoniazid group, while TNF-α production was highest in the NaCl group. The lowest values for these parameters were observed in mice treated with LFD. The number of cells producing TIMP1 was highest in the groups receiving LFD.
Conclusion. Two months after starting the isoniazid treatments, the amount of mycobacterium tuberculosis (MBT) in the liver decreased, particularly with the inhalational injection of LFD. This suggests that LFD helps modulate the inflammatory response in tissues and reduces damage, likely due to the systemic anti-inflammatory effect of oxidized dextran in the LFD.

1. Global tuberculosis report 2020. Geneva: World Health Organization; 2020. URL: https://apps.who.int/irLs/bitstream/hand le/10665/336069/9789240013131-eng.pdf [date of access: June 28, 2021].

2. Krasnova NM, Nikolaev VM. Isoniazid-induced liver injury: pharmacogenetic aspects. Russian Journal for Personalized Medicine. 2022; 2(3): 38-46. (In Russ.). doi: 10.18705/2782-3806-2022-2-3-38-46

3. Domingo-Gonzalez R, Prince O, Cooper A, Khader SA. Cytokines and chemokines in mycobacterium tuberculosis infection. Microbiol. Spectr. 2016; 4. doi: 10.1128/microbiolspec.TBTB2-0018-2016

4. Kumar NP, Moideen K, Banurekha VV, Nair D, Babu S. Plasma proinflammatory cytokines are markers of disease severity and bacterial burden in pulmonary tuberculosis. Open forum infectious diseases. – US: Oxford University Press. 2019; 6(7): ofz257. doi: 10.1093/ofid/ofz257

5. Rohlwink UK, Walker NF, Ordonez AA, Li YJ, Tucker EW, Elkington PT, et al. Matrix metalloproteinases in pulmonary and central nervous system tuberculosis — a review. International journal of molecular sciences. 2019; 20(6): 1350. doi: 10.3390/ijms20061350

6. Zharkov A, Shkurupy V, Lyadov E, Pevchenko B, Belyaev V, Troitsky A, et al. Evaluation of pharmacokinetic parameters and toxicity of anti-tuberculosis drug based on oxidized dextran and the hydrazide of isonicotinic acid. Medical Alliance. 2013; 1(4): 55-61. (In Russ.).

7. Shkurupy VA. Tuberculous granulomatosis. Cytophysiology and address therapy. Moscow: Izdatel’stvo RAMN; 2007: 536. (In Russ.).

8. Arkhipov SA, Shkurupiy VA, Neshadim DV, Akhramenko ES, Troitskiy AV, Iljin DA, et al. Study of biocompatibility liposomes with antituberculous drug (dekstrazid) in the macrophage cultures. International Journal of Applied and Fundamental Research. 2015; 9(1): 74-78. (In Russ.).

9. Sinyavskaya AM, Shkurupy VA, Troitskiy AV, Kovner AM. Location of pulmonary mycobacteria tuberculosis and effectiveness of various dextrazide compositions in treatment of mice with BCG induced granulomatosis. Bull. Exp. Biol. Med. 2020; 169(1): 63-66. doi: 10.1007/s10517-020-04825-6

10. Lillie RD. Histopathologic technic and practical histochemistry. N.Y.: Blakiston; 1954: 501.

11. Pagán AJ, Ramakrishnan L. Immunity and immunopathology in the tuberculous granuloma. Cold Spring Harbor perspectives in medicine. 2015; 5(9): a018499. doi: 10.1101/cshperspect.a018499

12. Kathamuthu GR, Kumar NP, Moideen K, Nair D, Banurekha VV, Sridhar R, et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are potential biomarkers of pulmonary and extra-pulmonary tuberculosis. Front. Immunol. 2020; 11: 419. doi: 10.3389/fimmu.2020.00419

13. Sabir N, Hussain T, Mangi MH, Zhao D, Zhou X. Matrix metalloproteinases: expression, regulation and role in the immunopathology of tuberculosis. Cell Prolif. 2019; 52(4): e12649. doi: 10.1111/cpr.12649

14. Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG. Metalloproteinases and their inhibitors: potential for the development of new therapeutics. Cells. 2020; 9(5): 1313. doi: 10.3390/cells9051313

15. Liu J, Khalil RA. Matrix metalloproteinase inhibitors as investigational and therapeutic tools in unrestrained tissue remodeling and pathological disorders. Prog Mol Biol Transl Sci. 2017; 148: 355-420. doi: 10.1016/bs.pmbts.2017.04.003

16. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. International journal of molecular sciences. 2020; 21(24): 9739. doi: 10.3390/cells9051313

17. Сhen Y, Wang J, Ge P, Cao D, Miao B, Robertson I, et al. Tissue inhibitor of metalloproteinases 1, a novel biomarker of tuberculosis. Mol. Med. Rep. 2017; 15(1): 483-487. doi: 10.3892/mmr.2016.5998

18. Troitsky AV, Cherdantseva LA, Bystrova TN, Novikova EG, Ukah HU, Grishin OV, et al. Role of oxidized dextran in prevention and control of viral pneumonia and pulmonary fibrosis. Acta Scientific Medical Sciences. 2023; 7(5): 164-172.

19. Guler R, Ozturk M, Sabeel S, Motaung B, Parihar SP, Thienemann F, et al. Targeting molecular inflammatory pathways in granuloma as host-directed therapies for tuberculosis. Front. Immun. 2021; 12: 733853. doi: 10.3389/fimmu.2021.733853