The Effects Of Triggering Receptor Expressed On Myeloid Cells Inhibitor LR12 On Airway Inflammation In Obese Asthmatic Mice

Objective:Obesity is a common comorbidity of asthma,and the interaction between the two often makes obese asthma symptoms severe and difficult to control.Obesity asthma often exhibits neutrophil inflammation and Th17 response and has poor efficacy for standard treatment regimens,and new treatment options are urgently needed.Triggering receptor expressed on myeloid cells-1(TREM-1)participates in innate and acquired immune responses and is associated with neutrophil inflammation and Th17 responses,which in turn drive the development of inflammation.Therefore,the aim of this study was to investigate the effects and possible mechanisms of TREM-1 expression in obese asthmatic mice and its inhibitor LR12 on airway inflammation in obese asthmatic mice.Methods:Female C57BL/6J mice,in accordance with weight,were divided into 5 groups at random: control group,asthma group,obese asthma group,LR12 treated group,dexamethasone treated group.(1)The total number of leukocytes and the ratio of neutrophils in BALF were calculated for each group of mice;(2)Lung pathological sections were made and then HE staining was used to notice the pathological changes;(3)ELISA was executed to determine the serum IL-17 A and IL-6 concentrations;(4)q PCR was applied to analyzed the relative m RNA expression levels of TREM-1 and IL-17 A in lung tissues;(5)The relative protein expression levels of NLRP3,Caspase1 p20 and IL-1β in lung tissues were compared through Western blot.Results:(1)At the end of the 8 weeks,the body weight of the mice on the high-fat diet exceeded that of the mice on the normal diet by 20%,and the hair was shiny and fat accumulated,suggesting that the obesity model was successfully constructed.The control group did not show any obvious abnormal performance throughout the experiment,but all other groups of mice showed different degrees of accelerated respiratory deepening and irritability when receiving OVA nebulization.The most obvious symptoms were in the obese asthma group,while the LR12 treated group and the dexamethasone treated group showed less symptoms than the obese asthma group.(2)The total leukocyte count and neutrophil ratio of BALF were significantly increased in the asthma and obese asthma groups compared to the control group,and more significantly in the obese asthma group.the total leukocyte count was significantly lower in the LR12 treated group and dexamethasone treated group compared to the obese asthma group.In addition,the neutrophil ratio was lower in the LR12 treated group compared to the obese asthma group(p<0.05),which was different from that in the dexamethasone treated group(p>0.05).(3)HE staining showed no significant inflammatory response around the airways in the control group,and increased airway injury and inflammatory cell infiltration in the asthma and obese asthma groups.The inflammatory response was more pronounced in the obese asthma group than in the asthma group.inflammation was reduced in the LR12 treated and dexamethasone treated groups compared with the obese asthma group.(4)ELISA results showed that serum IL-17 A and IL-6 concentrations were significantly higher in the asthma group and obese asthma group than in the control group,and the changes were more prominent in the obese asthma group,while the LR12 treated group and dexamethasone treated group were significantly lower than the obese asthma group(p<0.05).(5)The results of q PCR showed that the m RNA expressions of TREM-1 and IL-17 A in the lung tissue of mice in the asthma group and the obese asthma group were significantly higher than those in the control group,and it was more obvious in the obese asthma group.The LR12 treatment group was lower than the obese asthma group(p<0.05).(6)Western blot results showed that the expression of NLRP3,Caspase1 p20 and IL-1β protein in lung tissue of mice in asthma group and obese asthma group was significantly higher than that in control group,especially in obese asthma group.The expression levels of NLRP3 pathway-related proteins in the LR12 treatment group were lower than those in the obese asthma group(p<0.05).Conclusion:1.TREM-1 expression is upregulated in lung tissue of obese asthmatic mice and was involved in inflammatory infiltration.2.TREM-1 inhibitor LR12 can reduce the airway inflammation in obese asthmatic mice and decrease the serum IL-17 A and IL-6 levels.3.TREM-1 inhibitor LR12 can inhibit inflammation in obese asthmatic mice,and its underlying mechanism may be to reduce the activation of NLRP3 inflammasome,which may serve as a new therapeutic target for obese asthma.