常规树突状细胞靶向性的FLT3信号通路对急性肺损伤的调控  

FLT3 signaling manipulates conventional dendritic cells to regulate acute lung injury

作　　者：董亮[1] 徐静媛[1] 刘军[1] 陆晓旻[1] 杨毅[1] 邱海波[1] 

机构地区：[1]东南大学附属中大医院重症医学科,南京210009

出　　处：《中华医学杂志》2012年第43期3079-3084,共6页National Medical Journal of China

基　　金：国家自然科学基金（81070049）;江苏省“科教兴卫工程”医学重点学科项目（889-KJXW11.3）;国家临床重点专科建设项目（2100299）

摘　　要：目的明确常规树突状细胞（cDCs）靶向性的FMS样酪氨酸激酶3（FLT3）信号通路对急性肺损伤（ALI）早期炎症反应及肺损伤的调控效应及可能机制。方法C57BL／6小鼠随机分为正常对照组、ALI组、FLT3-配体（ligand）（FLT3L）预处理组、来他替尼预处理组和二甲基亚砜（DMSO）对照组，分别给予FLT3L、来他替尼预处理5d后复制Au模型，24h后处死小鼠留取肺组织，采用流式细胞术检测评价肺cDCs的数量和成熟程度；比色法检测髓过氧化物酶（MPO）活性反映中性粒细胞浸润；多聚酶链反应（PCR）检测转录因子T—bet／GATA-3mRNA比值反映Th1／Th2免疫反应平衡；计算肺湿重／体重比评价肺水肿程度；肺组织HE染色行组织病理学检查和肺损伤评分反映肺损伤程度。结果与正常对照组相比，ALI组小鼠肺cDCs的数量[（1．71％±0．35％）比（0．68％±0．15％）]及其MHCⅡ表达[（21．5％±4．5％）比（6．7％±2．8％）]和CD80表达[（31．2％±5．3％）比（7．3％±1．7％）]均显著增高（均P〈0．05）。与ALI组相比，FLT3L预处理进一步增加肺cDCs的数量[（2．81％±0．42％）比（1．71％±0．35％），P〈0．05]及其MHCⅡ表达[（40．8％±6．7％）比（21．5％±4．5％），P〈0．05]和CD80表达[（59．9％±8．1％）比（31．2％±5．3％），P〈0．05]，并上调肺组织MPO活性[（7．2±0．4）U／g比（5．3±0．6）U／g]及T—bet／GATA-3mRNA比值（％）[（600±222）比（220±48）]，加重肺水肿和肺损伤。与DMSO对照组相比，来他替尼预处理显著减少肺cDCs的数量[（0．90％±0．28％）比（1．65％±0，44％），P〈0，05]及其MHCII表达[（23，1％±3．1％）比（35．6％±6．2％），P〈0．05]和CD80表达[（22．9％±5．4％）比（43．3％±7．8％），P〈0．05]，并下调肺组织MPO活性[（4．3±0．3）U／g比（6．5±0．5）U／g]及T—bet／GATA-3mRNA比值[�Objective To explore the effects of FLT3 signaling on the accumulation and maturation of pulmonary conventional dendritic cells （cDCs） and determine whether or not the inhibition of FLT3 signaling may attenuate acute lung inflammation/injury （ALI）. Methods C57BL/6 mice were pretreated separately with FLT3-1igand （FLT3L） and lestaurtinib for 5 days. Murine model of ALI was subsequently induced by an intra-tracheal instillation of lipopolysaccharide （LPS） and lung specimens were harvested 24 hours later. The accumulation and maturation status of pulmonary cDCs were /tssessed by flow cytometry. Lung myeloperoxidase （MPO） activity was measured to evaluate the infiltration of neutrophils. The ratio between transcription factors T-bet and GATA-3 mRNA was determined to estimate the balance of Thl/Th2 response. Lung injury was estimated by lung wet weight/body weight ratio （LWW/BW） and histopathological assessment. Results LPS challenge resulted in rapid accumulation and maturation of pulmonary cDCs. FLT3L pretreatment further stimulated the accumulation and maturation of pulmonary cDCs, leading to a marked deterioration of LWW/BW and lung histopathological changes. Meanwhile, the lung MPO activity and T-bet/GATA-3 mRNA ratio were boosted by the administration of FLT3L In contrast, the lestaurtinib pretreatment inhibited the accumulation and maturation of pulmonary cDCs, leading to a significant improvement of LWW/BW and lung histopathological changes. The administration of lestaurtinib also suppressed the lung MPO activity and T-bet/GATA-3 mRNA ratio in the lung. Conclusions FLT3 signaling attenuates ALI by regulating the accumulation and maturation of pulmonary cDCs, indicating a potential pharmacotherapy for ALL.

关 键 词：呼吸窘迫综合征 成人型 炎症 树突细胞 蛋白质酪氨酸激酶 

分 类 号：R563.8[医药卫生—呼吸系统]