Leptin-deficient mice exhibit impaired host defense in gram-negative pneumonia
Leptin-deficient mice exhibit impaired host defense in gram-negative pneumonia
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DOI：
10.4049/jimmunol.168.8.4018
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发表时间：
2002-04-15
影响因子：
4.4
通讯作者：
Huffnagle, GB
中科院分区：
文献类型：
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作者：
Mancuso, P;Gottschalk, A;Huffnagle, GB
瘦素是一种脂肪细胞来源的激素，其分泌与全身脂质储存相关。血清瘦素水平降低的身体脂肪量的损失，将伴随着饥饿和营养不良。最近，瘦素已被证明可以调节先天性免疫反应，如巨噬细胞吞噬和细胞因子的合成在体外。为了确定瘦素是否在体内先天宿主对革兰氏阴性肺炎的反应中起作用，我们比较了瘦素缺陷型和野生型小鼠在肺炎克雷伯氏菌的肠道内攻击后的反应。继K。在给予肺炎链球菌后，我们观察到血清、支气管肺泡灌洗液和全肺匀浆中的瘦素水平增加。在一项生存研究中，与野生型小鼠相比，瘦素缺陷型小鼠在K。肺炎杆菌给药。对K.瘦素缺陷小鼠中的肺炎与体外细菌清除率降低和肺泡巨噬细胞吞噬功能缺陷有关。外源性添加极高水平的瘦素（500 ng/ml）可恢复肺泡巨噬细胞吞噬K。pneumoniae体外培养。而在K.给予肺炎克雷伯菌后，瘦素缺陷小鼠肺巨噬细胞中的白三烯合成减少。通过向体外巨噬细胞中加入外源性瘦素（500 ng/ml）来恢复白三烯的产生。这项研究首次表明，瘦素缺乏小鼠显示受损的宿主防御细菌性肺炎，这可能是由于肺泡巨噬细胞吞噬功能和白三烯合成的缺陷。
Leptin is an adipocyte-derived hormone that is secreted in correlation with total body lipid stores. Serum leptin levels are lowered by the loss of body fat mass that would accompany starvation and malnutrition. Recently, leptin has been shown to modulate innate immune responses such as macrophage phagocytosis and cytokine synthesis in vitro. To determine whether leptin plays a role in the innate host response against Gram-negative pneumonia in vivo, we compared the responses of leptin-deficient and wild-type mice following an intratracheal challenge of Klebsiella pneumoniae. Following K. pneumoniae administration, we observed increased leptin levels in serum, bronchoalveolar lavage fluid, and whole lung homogenates. In a survival study, leptin-deficient mice, as compared with wild-type mice, exhibited increased mortality following K. pneumoniae administration. The increased susceptibility to K. pneumoniae in the leptin-deficient mice was associated with reduced bacterial clearance and defective alveolar macrophage phagocytosis in vitro. The exogenous addition of very high levels of leptin (500 ng/ml) restored the defect in alveolar macrophage phagocytosis of K. pneumoniae in vitro. While there were no differences between wild-type and leptin-deficient mice in lung homogenate cytokines TNF-alpha, IL-12, or macrophage-inflammatory protein-2 after K. pneunioniae administration, leukotriene synthesis in lung macrophages from leptin-deficient mice was reduced. Leukotriene production was restored by the addition of exogenous leptin (500 ng/ml) to macrophages in vitro. This study demonstrates for the first time that leptin-deficient mice display impaired host defense in bacterial pneumonia that may be due to a defect in alveolar macrophage phagocytosis and leukotriene synthesis.