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

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.

Keywords

respiratory distress syndrome / interleukin-1 receptor antagonist / superoxide dismutase / bleomycin / injection administration / inhalation administration

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Funding

Федеральное медико-биологическое агентствоFederal Medical and Biological Agency(25.451.23.0)

RIGHTS & PERMISSIONS

Ischenko A.M., Nekrasova K.A., Laptev D.S., Bobkov D.V., Kolobov A.A., Simbirtsev A.S.