The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury.
The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury.
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DOI：
10.1097/ccm.0000000000000048
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发表时间：
2014-02
影响因子：
8.8
通讯作者：
Suratt BT
中科院分区：
文献类型：
--
作者：
Ubags ND;Vernooy JH;Burg E;Hayes C;Bement J;Dilli E;Zabeau L;Abraham E;Poch KR;Nick JA;Dienz O;Zuñiga J;Wargo MJ;Mizgerd JP;Tavernier J;Rincón M;Poynter ME;Wouters EF;Suratt BT
严重肺炎和相关急性肺损伤（ALI）的标志之一是中性粒细胞聚集到肺部。瘦素被认为在损伤后在肺中上调，并对白细胞产生不同的影响，影响趋化性和存活。我们假设肺瘦素直接促进肺炎和ALI期间肺嗜中性粒细胞的发展。对照人类和小鼠体内和离体实验研究。大学医院的研究实验室。健康人类志愿者和因细菌性和H1N1肺炎住院的受试者。还使用C57 B1/6和db/db小鼠。对细菌性肺炎或H1N1肺炎及相关ALI患者和小鼠的肺样本进行瘦素免疫染色。人支气管肺泡灌洗（BAL）样品后，脂多糖（LPS）诱导的肺损伤进行了测定瘦素。在口咽吸入单独的重组瘦素或重组瘦素与大肠杆菌或肺炎克雷伯菌诱导的肺炎的组合后，检查C57 B1/6小鼠。还使用大肠杆菌模型检查了瘦素抗性（db/db）小鼠。测量BAL嗜中性粒细胞和细胞因子水平。在体外人血液和小鼠骨髓来源的中性粒细胞中检查了瘦素诱导的趋化性。与正常肺相比，损伤的人和小鼠肺组织显示瘦素诱导，LPS滴注后的人BAL也是如此。未受伤和感染小鼠的BAL嗜中性粒细胞增多，肺细菌负荷减少气道瘦素管理，而感染瘦素耐药小鼠的BAL嗜中性粒细胞减少。在LPS致无菌性肺损伤中，瘦素也能减少肺泡中性粒细胞凋亡。人和鼠的中性粒细胞在体外都向瘦素迁移，这需要通过JAK 2/PI 3 K通路的完整信号传导。我们证明，肺瘦素诱导受伤的人类和小鼠肺，这种细胞因子是有效的驱动肺泡气嗜酸性粒细胞。这种作用似乎是由瘦素对中性粒细胞的直接作用引起的。
One of the hallmarks of severe pneumonia and associated Acute Lung Injury (ALI) is neutrophil recruitment to the lung. Leptin is thought to be up-regulated in the lung following injury and to exert diverse effects on leukocytes, influencing both chemotaxis and survival. We hypothesized that pulmonary leptin contributes directly to the development of pulmonary neutrophilia during pneumonia and ALI. Controlled human and murine in vivo and ex vivo experimental studies. Research laboratory of a university hospital. Healthy human volunteers and subjects hospitalized with bacterial and H1N1 pneumonia. C57Bl/6 and db/db mice were also used. Lung samples from patients and mice with either bacterial or H1N1 pneumonia and associated ALI were immunostained for leptin. Human bronchoalveolar-lavage (BAL) samples obtained after lipopolysaccharide (LPS)-induced lung injury were assayed for leptin. C57Bl/6 mice were examined after oropharyngeal aspiration of recombinant leptin alone or in combination with E.coli- or K.pneumonia-induced pneumonia. Leptin-resistant (db/db) mice were also examined using the E.coli model. BAL neutrophilia and cytokine levels were measured. Leptin-induced chemotaxis was examined in human blood- and murine marrow-derived neutrophils in vitro. Injured human and murine lung tissue showed leptin induction compared to normal lung, as did human BAL following LPS instillation. BAL neutrophilia in uninjured and infected mice was increased and lung bacterial-load decreased by airway leptin administration, whereas BAL neutrophilia in infected leptin-resistant mice was decreased. In sterile lung injury by LPS, leptin also appeared to decrease airspace neutrophil apoptosis. Both human and murine neutrophils migrated towards leptin in vitro, and this required intact signaling through the JAK2/PI3K pathway. We demonstrate that pulmonary leptin is induced in injured human and murine lungs and that this cytokine is effective in driving alveolar airspace neutrophilia. This action appears to be caused by direct effects of leptin on neutrophils.