Effects Of R-salbutamol On Imiquimod Induced Psoriasis,It's Mechanism And Metabolomics Study

Psoriasis is a common chronic autoimmune disease,which is diagnosed by the clinical criteria of well-defined,uplifted erythema,covered by silver-white scales,and has great physical and psychological burden on patients due to its visibility of symptoms and frequent association with itching and pain.There is a lack of safe,effective and economical drugs for the treatment of psoriasis.R-salbutamol is a commercially available drug of racemic salbutamol,which is used for the treatment of asthma and with high safety in clinic.Our previous experiments showed that R-sal could inhibit and modulate the immune inflammation of respiratory system,and play a role in the treatment of eczema and systemic lupus erythematosus.The aim of this study was to investigate the therapeutic effect of levosalbutamol on psoriasis by R-sal,and to investigate its mechanism and metabonomics.The main contents and research results are as follows:1.In this study,we investigated the anti-psoriatic effects of R-salbutamol in an IMQ-induced lesion model of mice with psoriasis.According to the behavioral evaluation,R-salbutamol intervention was found to reduce the PASI scores in mice;histopathological evaluation was founded that R-salbutamol intervention reduced the abnormal keratinocyte proliferation and Baker score in mice dorsal skin;automated five-category blood analysis showed R-salbutamol reduced inflammatory cell infiltration in the blood,especially the number of neutrophils and monocytes;enzyme-linked immunosorbent assay(ELISA)found R-salbutamol reduced the content of IL-17 produced by neutrophils and Th17 cells;and flow cytometry showed R-salbutamol reduced the number of Th17 cells in mouse spleen mononucleucocytes,increasing the number of Th cells and Treg cells.The reason may be related to the regulation of Th17/Tregs balance and the reduction of IL-17 level.2.A non-targeted metabolomics method of the UHPLC-Tims-Tof-MS/MS technique for the study of two-phase metabolites was used to study the mechanism of R-sal on psoriasis mice.The effects of R-sal on psoriasis mice were investigated from the plasma of mice,and the related metabolic pathways were elucidated.Through multivariate statistical analysis and structural identification,39 different metabolites in mouse plasma were found,mainly involving glycerol phospholipid metabolism,arachidonic acid metabolism and sphingomyelin metabolism.After administration of R-salbutamol,the expression of identified biomarkers tends to be normal,indicating R-salbutamol may play an anti-psoriasis role by regulating the concentrations of PC and PS,reducing arachidonic acid pathway and inhibiting the role of sphingomyelin.3.(R)-salbutamol significantly inhibited LPS-induced M1 macrophage polarization and downregulated expressions of typical M1 macrophage cytokines,including monocyte chemotactic protein-1,interleukin-1? and tumour necrosis factor a.At the same time,(R)-salbutamol significantly decreased the production of inducible enitricoxidesyn-thase(iNOS),nitricoxide(NO)and reactive oxygen species(ROS),while increasing the reduced glutathione(GSH)/oxidized glutathione(GSSG)ratio.Bioenergetic profiles showed that(R)-salbutamol significantly reduced aerobic glycolysis and enhanced mitochon-drial respiration.The effects of(R)-salbutamol on M1 polarization were inhibited by a specific ?2 receptor antagonist,ICI-118551.4.Untargeted metabolomics analysis demonstrated that 11 specific biomarkers and three pathways of(R)-salbutamol modulated metabolic pathways was found,namely,(a)phenylalanine metabolism,(b)the pentose phosphate pathway and(c)glycerophos-pholipid metabolism,of which glycerophospholipid metabolism is the most influential pathway.In summary,(R)-salbutamol can effectively improve psoriasis-like lesions at molecular,energy and metabolic levels,increase the proportion of Treg cells by reducing the concentration of neutrophils,inhibiting the transformation of macrophages to M1 and the transformation of naive T cells to Th17,regulating the glycerol phospholipid metabolism,arachidonic acid metabolism,sphingomyelin metabolism,phenylalanine metabolism and pentose phosphate pathway.