Intrapulmonary tumor necrosis factor gene therapy increases bacterial clearance and survival in murine gram-negative pneumonia.
Intrapulmonary tumor necrosis factor gene therapy increases bacterial clearance and survival in murine gram-negative pneumonia.
复制标题
肺内肿瘤坏死因子基因治疗可增加小鼠革兰氏阴性肺炎的细菌清除率和存活率。
DOI：
10.1089/10430349950018300
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发表时间：
1999
影响因子：
4.2
通讯作者：
Moore,TA
中科院分区：
文献类型：
--
作者：
Standiford,TJ;Wilkowski,JM;Sisson,TH;Hattori,N;Mehrad,B;Bucknell,KA;Moore,TA
肿瘤坏死因子α（TNF）已被证明是细菌性肺炎中先天免疫的重要细胞因子介质。为了增加TNF在肺内的表达， 已经开发了含有鼠TNF cDNA的载体（Ad 5 mTNF），并且该载体的气管内施用导致TNF在肺中的剂量和时间依赖性表达，但不是全身性的。 Ad 5 mTNF给药导致显著的气道和支气管周围炎症，治疗后2天主要是中性粒细胞流入，4 - 7天出现单核细胞浸润。 重要的是，以1 × 10 - 8 PFU的剂量施用Ad 5 mTNF显著改善了伴随肺炎克雷伯氏菌攻击的动物的存活率，这与 增强了肺部细菌的清除，减少了K.肺炎病毒进入血液然而，递送更高剂量的Ad 5 mTNF（5 × 10 - 8 PFU）并不是有益的，事实上， 气管内施用类似剂量的对照载体（Ad 5LacZ）实际上通过损害K的清除而增强了克雷伯氏菌诱导的致死性。肺炎从肺部。我们的研究表明 TNF在肺内的瞬时转基因表达剂量依赖性地增强鼠肺炎克雷伯氏菌中的抗菌宿主防御。
Tumor necrosis factor alpha (TNF) has been shown to be an essential cytokine mediator of innate immunity in bacterial pneumonia. To augment the expression of TNF within the lung, a recombinant adenoviral vector containing the murine TNF cDNA (Ad5mTNF) has been developed, and the intratracheal administration of this vector resulted in the dose- and time-dependent expression of TNF in the lung, but not systemically. Administration of Ad5mTNF resulted in significant airspace and peribronchial inflammation, with a predominant neutrophil influx by 2 days, and mononuclear cell infiltrates by 4 to 7 days posttreatment. Importantly, the administration of Ad5mTNF at a dose of 1 X 10 8 PFU significantly improved the survival of animals challenged concomitantly with Klebsiella pneumoniae, which occurred in association with enhanced clearance of bacteria from the lung and decreased dissemination of K. pneumoniae to the bloodstream. However, the delivery of higher doses of Ad5mTNF (5 X 10 8 PFU) was not beneficial and in fact the intratracheal administration of a similar dose of control vector (Ad5LacZ) actually enhanced Klebsiella -induced lethality by impairing clearance of K. pneumoniae from the lung. Our studies suggests that the transient transgenic expression of TNF within the lung dose dependently augments antibacterial host defense in murine Klebsiella pneumonia.