Intrapulmonary tumor necrosis factor gene therapy increases bacterial clearance and survival in murine gram-negative pneumonia

被引:57
作者
Standiford, TJ [1 ]
Wilkowski, JM [1 ]
Sisson, TH [1 ]
Hattori, N [1 ]
Mehrad, B [1 ]
Bucknell, KA [1 ]
Moore, TA [1 ]
机构
[1] Univ Michigan, Med Ctr, Div Pulm & Crit Care Med, Dept Med,Med Sch, Ann Arbor, MI 48109 USA
关键词
D O I
10.1089/10430349950018300
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Tumor necrosis factor (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,vith 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.
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页码:899 / 909
页数:11
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