Effectiveness of various regimens of systemic anti-inflammatory therapy with glucocorticoids in the development of acute LPS-induced lung damage in the experiment

Abstract

BACKGROUND: When studying new and effective methods of treating acute respiratory distress syndrome, an immunogenic model of lung injury occupies a special place. To date, the search for the optimal strategy and regimen for the use of glucocorticoids in the development of acute respiratory distress syndromе is relevant.

AIM: The article evaluates the effectiveness of various schemes of systemic anti-inflammatory therapy with glucocorticoids in an experimental model of acute LPS-induced lung injury.

MATERIALS AND METHODS: The study was conducted on 100 outbred male rats. Acute lung injury was modeled using an experimental model of direct acute lung injury by a single intratracheal injection of lipopolysaccharide (LPS) from the cell wall of the bacterium Salmonella enterica (Sigma-Aldrich) at a dose of LD50 (20 mg/kg). All animals were divided into groups (20 each): 1 — intact rats; 2 — control group (LPS + saline); 3 — LPS + dexamethasone 0.52 mg/kg (small doses); 4 — LPS + dexamethasone 1.71 mg/kg (average doses); 5 — LPS + dexamethasone 8 mg/kg (high doses). The drugs were administered intraperitoneally once a day for 3 days. Dexamethasone doses were calculated using the interspecies dose transfer method using a factor that takes into account differences in body surface area.

RESULTS: It has been established that an experimental model based on the endotracheal administration of S. enterica leads to the development of mortality from pulmonary causes. According to a preclinical study, the systemic use of low doses of dexamethasone (0.52 mg/kg) was found to be better than higher doses (1.71 mg/kg, 8 mg/kg) in the treatment of acute LPS-induced lung injury.

Keywords

acute lung injury / acute respiratory distress syndrome / dexamethasone / glucocorticoids / immunogenic model of lung injury / lipopolysaccharide / preclinical study

References

[1] Salukhov VV, Kharitonov MA, Kryukov EV, et al. Topical issues of diagnostics, examination and treatment of patients with COVID-19-associated pneumonia in different countries and continents. Medical Council. 2020;(21):96–102. (In Russ.) DOI: 10.21518/2079-701X-2020-21-96-102

[2] Салухов В.В., Харитонов М.А., Крюков Е.В., и др. Актуальные вопросы диагностики, обследования и лечения больных с COVID-19-ассоциированной пневмонией в различных странах и континентах // Медицинский Совет. 2020. № 21. С. 96–102. DOI: 10.21518/2079-701X-2020-21-96-102

[3] Gritsan AI, Yaroshetskiy AI, Vlasenko AV, et al. Diagnostics and intensive therapy of acute respiratory distress syndrome. FAR’s clinical guidelines. Russian Journal of Anаеsthesiology and Reanimatology. 2016;61(1):62–70. (In Russ.) DOI: 10.17116/anaesthesiology20200215

[4] Грицан А.И., Ярошецкий А.И., Власенко А.В., и др. Диагностика и интенсивная терапия острого респираторного дистресс-синдрома. Клинические рекомендации ФАР // Анестезиология и реаниматология. 2016. Т. 61, № 1. С. 62–70. DOI: 10.17116/anaesthesiology20200215

[5] Zvyagintsev DP, Shperling MI. On the issue of systemic endothelial dysfunction in patients with severe COVID-19 and the presence of acute respiratory distress syndrome. Russian Military Medical Academy Reports. 2021;40(S1–3):116–121. (In Russ.)

[6] Звягинцев Д.П., Шперлинг М.И. К вопросу о системности эндотелиальной дисфункции у больных с тяжелым течением COVID-19 и наличием острого респираторного дистресс-синдрома // Известия Российской Военно-медицинской академии. 2021. Т. 40, № S1–3. С. 116–121.

[7] Pugach VA, Tyunin MA, Ilinskiy NS, et al. An experimental model of direct acute lung injury in rats caused by intratracheal administration of lipopolysaccharide from salmonella enterica. Journal Biomed. 2021;17(3):84–89. (In Russ.) DOI: 10.33647/2074-5982-17-3-84-89

[8] Пугач В.А., Тюнин М.А., Ильинский Н.С., и др. Экспериментальная модель прямого острого повреждения легких у крыс, вызванного интратрахеальным введением липополисахарида Salmonella enterica // Биомедицина. 2021. Т. 17, № 3. С. 84–89. DOI: 10.33647/2074-5982-17-3-84-89

[9] Korovin AE, Novitskiy AA, Makarov DA. Acute respiratory distress syndrome. Current state of the problem. Clinical pathophysiology. 2018;24(2):32–41. (In Russ.)

[10] Коровин А.Е., Новицкий А.А., Макаров Д.А. Острый респираторный дистресс-синдром. Современное состояние проблемы // Клиническая патофизиология. 2018. Т. 24, № 2. С. 32–41.

[11] Yubero S, Manso MA, Ramudo L, et al. Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models. Pulmonary pharmacology and therapeutics. 2012;25(4):319–324. DOI: 10.1016/j.pupt.2012.05.009

[12] Yubero S., Manso M.A., Ramudo L., et al. Dexamethasone down-regulates the inflammatory mediators but fails to reduce the tissue injury in the lung of acute pancreatitis rat models // Pulmonary pharmacology and therapeutics. 2012. Vol. 25. No. 4. Р. 319–324. DOI: 10.1016/j.pupt.2012.05.009

[13] Mikolka P, Kosutova P, Kolomaznik M, et al. Effect of different dosages of dexamethasone therapy on lung function and inflammation in an early phase of acute respiratory distress syndrome model. Physiological research. 2019;68(Suppl 3):253–263. DOI: 10.33549/physiolres.934364

[14] Mikolka P., Kosutova P., Kolomaznik M., et al. Effect of different dosages of dexamethasone therapy on lung function and inflammation in an early phase of acute respiratory distress syndrome model // Physiological research. 2019. Vol. 68, Suppl 3. P. 253–263. DOI: 10.33549/physiolres.934364

[15] Shekunova EV, Kovaleva MA, Makarova MN, Makarov VG. Dose Selection in Preclinical Studies: Cross-Species Dose Conversion. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2020;10(1):19–28. (In Russ.) DOI: 10.30895/1991-2919-2020-10-1-19-28

[16] Шекунова Е.В., Ковалева М.А., Макарова М.Н., Макаров В.Г. Выбор дозы препарата для доклинического исследования: межвидовой перенос доз // Ведомости Научного центра экспертизы средств медицинского применения. 2020. Т. 10, № 1. С. 19–28. DOI: 10.30895/1991-2919-2020-10-1-19-28

RIGHTS & PERMISSIONS

Salukhov V.V., Voloshin N.I., Shperling M.I.