IL-1 Receptor Antagonist as an Aerosol in Inflammation

Abstract

The feasibility of efficient aerosol delivery of the human IL-1 receptor antagonist (IL-1Ra) for reduction of acute lung inflammation was demonstrated in a mouse model study. The therapeutic efficacy of dry powder formulations PM₂, PM₁₀ of IL-1Ra was studied at nonforced inhalation in an aerosol chamber using the DPI “Spinhaler”. Micronized powder formulations for insufflation were produced by air-jet milling. The anti-inflammatory effect of IL-Ra preparation was assessed by differential cell counts and biochemical composition of bron-choalveolar lavage (BAL). Reactive oxygen species (ROS), metabolic parameters of BAL (pH, redox potential, total protein, and lactate), and morphological lung changes were investigated by methods of luminol-dependent chemoluminescence, electrochemistry, microscopy, optical, and NMR spectroscopy. Inhalation of IL-1Ra aerosol ensured the systemic absorption of IL-1Ra in the circulatory system and reduced the acute inflammatory response to intranasal lipopolysaccharide challenge. The inhaled anti-inflammatory dosage in aerosol administration appeared to be comparable with i.p. injection. The mechanism of positive action of pulmonary aerosol delivery of Il-Ra includes normalization of the oxidative activity of bron-choalveolar cells, prevention of neutrophil recruitment to the bronchoalveolar tract, and improving of cell respiration. The results were used to develop mathematical models of the anti-inflammatory effects of IL-Ra as functions of the doses and dispersion grades of IL-Ra preparations. Aerosol application of IL-Ra may be an apparent way for prophylactic treating of respiratory inflammation caused by bacterial antigens.