vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2024-21-3-219-230vestim-984Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEСостояние внеклеточного матрикса селезенки при введении липосомальной формы декстразида мышам в периоде хронического БЦЖ-индуцированного гранулематозаLiposome-encapsulated dextrazide modifies spleen extracellular matrix composition in mice with chronic BCG-induced inflammationhttps://orcid.org/0000-0002-4051-8854КимЛ. Б.KimL. B.

Ким Лена Борисовна – д-р мед. наук, гл. науч. сотрудник, руководитель группы

ул. Тимакова, 2, 630117, г. Новосибирск

Lena B. Kim – D. Sc. (Med.), Chief Researcher, Head of the group

2, Timakov Str., 630117, Novosibirsk

lbkim@frcftm.ruhttps://orcid.org/0000-0001-9599-3049ПутятинаА. Н.PutyatinaA. N.

Путятина Анна Николаевна – канд. мед. наук, науч. сотрудник

ул. Тимакова, 2, 630117, г. Новосибирск

Anna N. Putyatina – Ph. D. (Med.), Researcher

2, Timakov Str., 630117, Novosibirsk

anputyatina@frcftm.ruhttps://orcid.org/0000-0003-1565-5248РусскихГ. С.RusskikhG. S.

Русских Галина Сергеевна – канд. биол. наук, ст. науч. сотрудник

ул. Тимакова, 2, 630117, г. Новосибирск

Galina S. Russkikh – Ph. D. (Biol.), Senior Researcher

2, Timakov Str., 630117, Novosibirsk

russkikh_g@mail.ruhttps://orcid.org/0000-0001-9407-5377ТроицкийА. В.TroitskijA. V.

Троицкий Александр Васильевич – канд. мед. наук, вед. науч. сотрудник, руководитель лаборатории

ул. Тимакова, 2, 630117, г. Новосибирск

Aleksandr V. Troitskij – Ph. D. (Med.), Leading Researcher, Head of the Laboratory

2, Timakov Str., 630117, Novosibirsk

pharm2008@yandex.ruФедеральный исследовательский центр фундаментальной и трансляционной медициныFederal Research Center of Fundamental and Translational Medicine202403092024213219230Copyright © Ким Л.Б., Путятина А.Н., Русских Г.С., Троицкий А.В., 20242024Ким Л.Б., Путятина А.Н., Русских Г.С., Троицкий А.В.Kim L.B., Putyatina A.N., Russkikh G.S., Troitskij A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/984

Фиброз паренхиматозных органов является распространенным осложнением туберкулеза. На модели БЦЖ-индуцированного воспаления у мышей продемонстрированы изменения метаболизма внеклеточного матрикса (ВКМ) селезенки при введении липосомальной формы декстразида (ЛФДЗ), содержащей изониазид и окисленный декстран.

Мыши были разделены на 4 группы: 1 – интактные животные; 2 – инфицированные мыши после однократного внутривенного введения вакцины БЦЖ; 3 ‒ животные, которым через 6 мес. после инфицирования в течение 3 мес. вводили раствор ЛФДЗ внутриперитонеально; 4 – мыши, которым вводили то же, что и животным группы 3, но ингаляционно. У мышей группы 2 обнаружены признаки выраженного фиброза селезенки (повышенное содержание гиалуронана, фракций гидроксипролина) при активации гиалуронидаз, матриксных металлопротеиназ (ММП), α2-макроглобулина и повышенном содержании тканевых ингибиторов ММП (TИМП-1 и TИМП-2) относительно данных группы 1. В группе 3 отмечены изменения в структуре протеогликанов (увеличение содержания уроновых кислот и галактозы), снижение уровней гиалуронана и свободного гидроксипролина, повышение активности гиалуронидаз. Активность ММП и содержание ТИМП соответствовали показателям в группе 2. В группе 4 также увеличилось содержание уроновых кислот и галактозы в протеогликанах, но отмечалось снижение уровня пептидно-связанного гидроксипролина и более заметным было снижение содержания гиалуронана. Активность всех ферментов, регулирующих метаболизм ВКМ, была снижена относительно показателей в группе 2.

Таким образом, внутриперитонеальное введение ЛФДЗ инфицированным мышам привело к активации гиалуронидаз, изменению структуры протеогликанов, снижению содержания свободного гидроксипролина. Ингаляционное введение ЛФДЗ наряду с изменениями структуры протеогликанов снижало активность ММП, гиалуронидаз, α2-макроглобулина, а также содержание ТИМП-1 и ТИМП-2, пептидно-связанного гидроксипролина. Антифибротический эффект ЛФДЗ проявился в снижении уровня пептидно-связанного гидроксипролина и в более значимом снижении содержания гиалуронана при ингаляционном введении, чем при внутриперитонеальном.

Fibrosis of parenchymal organs is a common complication of tuberculosis. In a model of BCG-induced inflammation in mice, changes in the metabolism of the extracellular matrix (ECM) of the spleen were demonstrated with the introduction of a liposome-encapsulated dextrazide (LEDZ) containing isoniazid and oxidized dextran.

The mice were divided into 4 groups: 1 – intact animals; 2 – infected mice after a single intravenous injection of BCG vaccine. 6 mo after infection, a solution of LEDZ was administered intraperitoneally to mice of group 3 for 3 mo, and inhaled to mice of group 4. Group 2 mice showed the signs of pronounced spleen fibrosis (increased content of hyaluronan, hydroxyproline fractions) with activation of hyaluronidases, matrix metalloproteinases (MMP), α2-macroglobulin and an increased content of tissue inhibitors of MMP (TIMP-1 and TIMP-2) with respect to group 1 data. In group 3, changesin the structure of proteoglycans were noted (an increase in the content of uronic acids and galactose), a decrease in the content of hyaluronan and free hydroxyproline, an increase in the activity of hyaluronidases. The MMP activity and the TIMP content corresponded to the data of group 2. In group 4, the content of uronic acids and galactose in proteoglycans also increased, but peptide-bound hydroxyproline decreased and the hyaluronan content more noticeably decreased. The activity of all enzymes regulating the ECM metabolism reduced with respect to the data of group 2.

Thus, intraperitoneal administration of LEDZ to infected mice led to activating hyaluronidases, changing the structure of proteoglycans, and decreasing the free hydroxyproline content. Inhalation administration of LEDZ, along with changes in the structure of proteoglycans, reduced the activity of MMP, hyaluronidases, α2-macroglobulin, the content of TIMP-1 and TIMP-2, peptide-bound hydroxyproline. The antifibrotic effect of LEDZ with inhalation administration was manifested in a decrease in peptide-bound hydroxyproline and in a more significant decrease in hyaluronan compared with intraperitoneal administration.

Thus, intraperitoneal administration of LEDZ to infected mice led to activating hyaluronidases, changing the structure of proteoglycans, and decreasing the free hydroxyproline content. Inhalation administration of LEDZ, along with changes in the structure of proteoglycans, reduced the activity of MMP, hyaluronidases, α2-macroglobulin, the content of TIMP-1 and TIMP-2, peptide-bound hydroxyproline. The antifibrotic effect of LEDZ with inhalation administration was manifested in a decrease in peptide-bound hydroxyproline and in a more significant decrease in hyaluronan compared with intraperitoneal administration.

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The authors declare that there are no conflicts of interest present.