Effect of local suppression of Stat3 gene expression in a mouse model of pulmonary neutrophilic inflammation
Introduction. Bronchial asthma (BA) is a chronic inflammatory disease of the airways. For a long time, it was believed that BA developed exclusively according to the Th2-dependent mechanism, however, to date, several phenotypes of the disease have been distinguished, one of which is neutrophilic BA. Neutrophilic BA is characterized by resistance to standard corticosteroid therapy, that need to search for new way of treatment. Neutrophilic inflammation of the lungs is developed under activation of IL-6/STAT3-pathway, that makes the molecular components of this pathway to be the promising targets. One of the technologies by which genes expression can be regulated is RNA interference. The aim of this study was to evaluate the effects of local suppression of Stat3 gene expression in a mouse model of neutrophilic BA. Material and methods. During the development of BA features mice were inhaled with a complex of small interfering RNA (siRNA) and a carrier peptide. After the course of inhalations, the severity of BA manifestations was assessed: the level of allergen-specific antibodies, changes in bronchial hyperreactivity, the cellular composition of the bronchoalveolar lavage (BAL) fluid, histopathological alterations in the lungs. Results. 5 variants of siRNA against Stat3 gene were designed. In vitro experiments established that the variant siSTAT3-1426 significantly (5 times) reduced the expression of the target gene. A complex of siRNA and a carrier peptide LTP down-regulated the expression of Stat3 and Il17a genes in Th17-lymphocytes. In vivo studies in a mouse model of neutrophilic BA revealed, that the inhalations with the complex led to a 2-fold inhibition of Stat3 gene expression in BAL fluid cells, 3-fold decrease in neutrophilic infiltration of the lungs and recovery of the thickness of the airway walls. Conclusion. The complex of siRNA targeted to Stat3 gene and the carrier peptide was developed. The inhalations with the complex decreased Th17-dependent neutrophilic inflammation of the lungs in neutrophilic BA model in mice, that can be a promising approach to the therapy of neutrophilic corticosteroid-resistant BA.