Study of Recombinant Interleukin-1 Receptor Antagonist Compositions Biological Activity After Injection and Inhalation in Mouse Model of Pulmonary Inflammation

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Abstract

BACKGROUND: The severity of respiratory distress syndrome is associated with the development of systemic multifactorial inflammatory processes leading to hyperinflammation. Proinflammatory cytokines, primarily interleukin-1 (IL-1), and reactive oxygen species substantially contribute to these pathological processes. The use of an interleukin-1 receptor antagonist (IL-1Ra) as an IL-1 blocker is a key first-line therapy for patients experiencing cytokine storm syndrome. The novelty of the approach under investigation lies in studying the effectiveness of inhaled administration of IL-1Ra, including its combined use with a reactive oxygen species inhibitor — superoxide dismutase (SOD).

AIM: To assess the efficacy of IL-1Ra administered parenterally and by inhalation, both as a standalone agent and in combination with SOD, in a bleomycin-induced acute respiratory distress syndrome model.

MATERIALS AND METHODS: Male BALB/c mice were used in the study. Respiratory distress syndrome was modeled by intraperitoneal administration of bleomycin at a dose of 2 mg/mouse on days 1, 8, and 15 of the experiment. The investigational drugs—a 10.0-mg/mL IL-1Ra solution and a 10.0-mg/mL IL-1Ra solution containing 0.4 mg/mL SOD—were administered to the experimental groups either subcutaneously or by inhalation at a dose of 2 mg/mouse daily for 15 days starting from day 1 of the experiment. Body weight, spirometry, histological studies, and animal survival were assessed.

RESULTS: Subcutaneous and inhalation administration of IL-1Ra + SOD, as well as subcutaneous administration of IL-1Ra, positively affected animal survival. Subcutaneous administration of IL-1Ra and IL-1Ra + SOD led to statistically significant improvements in indicators of external respiration in mice with bleomycin-induced intoxication. A reduction in destructive lung changes caused by intraperitoneal administration of bleomycin was observed in the experimental groups receiving inhaledIL-1Ra orIL-1Ra + SOD and in the group receiving subcutaneous IL-1Ra.

CONCLUSION: Both investigational products — IL-1Ra and IL-1Ra + SOD — administered by injection or inhalation demonstrated a positive effect in the treatment of respiratory distress syndrome induced by bleomycin in the mouse model.

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About the authors

Alexander M. Ischenko

State Research Institute of Highly Pure Biopreparations

Email: amischenko1946@mail.ru
ORCID iD: 0000-0002-6661-6145
SPIN-code: 5860-4216

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Ksenia A. Nekrasova

State Research Institute of Highly Pure Biopreparations

Author for correspondence.
Email: k.a.nekrasova@hpb.spb.ru
ORCID iD: 0000-0002-0242-9615
SPIN-code: 9435-6100

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Denis S. Laptev

Research Institute of Hygiene, Occupational Pathology and Human Ecology

Email: laptev@gpech.ru
ORCID iD: 0000-0002-3960-3058
SPIN-code: 2873-5071

Cand. Sci. (Biology)

Russian Federation, Saint Petersburg

Dmitry V. Bobkov

Research Institute of Hygiene, Occupational Pathology and Human Ecology

Email: bobkov@gpech.ru
ORCID iD: 0000-0003-3989-0437
SPIN-code: 2673-8240
Russian Federation, Saint Petersburg

Alexander A. Kolobov

Research Institute of Hygiene, Occupational Pathology and Human Ecology

Email: aak1959@internet.ru
ORCID iD: 0000-0002-9222-6773
SPIN-code: 7019-2420

Dr. Sci. (Biology)

Russian Federation, Saint Petersburg

Andrey S. Simbirtsev

State Research Institute of Highly Pure Biopreparations

Email: a.s.simbirtsev@hpb.spb.ru
ORCID iD: 0000-0002-8228-4240
SPIN-code: 2064-7584

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Saint Petersburg

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Supplementary files

Supplementary Files
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2. Fig. 1. Number of animal deaths after subcutaneous (s.c.) and inhalation (inh.) course administration of IL-1Ra (Ra) and IL-1Ra + SOD (Ra + SOD) against the background of triple intraperitoneal administration of bleomycin. Arrows indicate the days of bleomycin administration. SOD, superoxide dismutase.

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3. Fig. 2. Amplitude of air flow pressure changes (mm H2O) after subcutaneous (s.c.) and inhalation (inh.) course administration of IL-1Ra (Ra) and IL-1Ra + SOD (Ra + SOD) against the background of triple intraperitoneal administration of bleomycin. SOD, superoxide dismutase. * Statistically significant differences from the intact group (p ≤ 0.05, Mann–Whitney test); α, statistically significant differences from the saline group (p ≤ 0.05, Mann–Whitney test).

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4. Fig. 3. Rate of increase in air flow pressure during exhalation (mm H₂O/s) after subcutaneous (s.c.) and inhalation (inh.) course administration of IL-1Ra (Ra) and IL-1Ra + SOD (Ra + SOD) against the background of triple intraperitoneal administration of bleomycin. SOD, superoxide dismutase. * Statistically significant differences from the intact group (p ≤ 0.05, Mann–Whitney test); α, statistically significant differences from the saline group (p ≤ 0.05, Mann–Whitney test).

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Copyright (c) 2024 Ischenko A.M., Nekrasova K.A., Laptev D.S., Bobkov D.V., Kolobov A.A., Simbirtsev A.S.

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