Critical Role Of LTB4/BLT1/SOCS1 Pathway In Inflammation In Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease(COPD)is a chronic inflammatory disease of the airways that is characterized by progressive and irreversible decline in lung function,excessive mucus secretion and limited airflow.It causes significant social and economic burden and is a serious public health issue.Cigarette smoking(CS)is the main risk factor for COPD and persistent airway inflammation,and we focused on the mechanism of chronic inflammation that CS caused in our study,and our results may provide experimental evidence for the underlying mechanisms of COPD pathogenesis and a novel therapeutic approach for COPD.Evidence suggests that suppressor of cytokine signaling 1(SOCS1)is crucial for the negative regulation of inflammation,and leukotriene B4(LTB4)can lead to the degradation of SOCS1,when it combines with its receptor,BLT1.Thus,we hypothesis that the deficiency of SOCS1 in COPD patients may cause the chronic airway inflammation,then,we investigate the relationship between LTB4/BLT1/SOCS1 pathway and inflammation in vitro and in clinical samples of COPD.In the first part,we obtained endobronchial biopsies(15 COPD patients and 12 non-COPD control subjects)and bronchoalveolar lavage fluid(BALF)(20 COPD patients and 20 non-COPD control subjects),SOCS1 expression in bronchial mucosa and the level of cytokines in BLAF was determined,then,we investigated the relationship between SOCS1 expression and LTB4 level and FEV1%Pred of lung function.In the second part,we investigated the expression of SOCS1 in CSE-induced mouse macrophage cell line RAW264.7 cell,and detected the level of cytokines in the supernatant,then,we investigated the effects of BLT1 antagonist U-75302 on SOCS1 expression level of cytokines in these cells.In the first part,our results showed that SOCS1 expression significantly decreased in lung tissues and alveolar macrophages from COPD patients.Inflammatory cytokines in BALF were higher in COPD and LTB4 levels were negatively correlate with SOCS1 levels,besides,SOCS1 expression was positively correlate with FEV1%Pred.In the second part,the results illustrated that the express of SOCS1 significantly decreased and inflammatory cytokines increased when CSE treated,besides,the BLT1 antagonist restored SOCS1 expression and in turn inhibited inflammatory cytokine secretion in vitro.In conclusion,long-term cigarette smoke exposure induced SOCS1 degradation and LTB4 accumulation,which was associated with emphysema and inflammation.Thus,a BLT1 antagonist might be a potential therapeutic candidate for the treatment of COPD.