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

Tumor necrosis factor (TNF) has been shown to be an essential cytokine medi ator of innate immunity in bacterial pneumonia, To augment the expression o f TNF within the lung, a recombinant adenoviral vector containing the murin e TNF cDNA (Ad5mTNF) has been developed, and the intratracheal administrati on of this vector resulted in the dose- and time-dependent expression of TN F in the lung, but not systemically, Administration of Ad5mTNF resulted in significant airspace and peribronchial inflammation, with a predominant neu trophil influx by 2 days, and mononuclear cell infiltrates by 4 to 7 days p osttreatment. Importantly, the administration of Ad5mTNF at a dose of 1 x 1 0(8) PFU significantly improved the survival of animals challenged concomit antly,vith Klebsiella pneumoniae, which occurred in association with enhanc ed clearance of bacteria from the lung and decreased dissemination of K. pn eumoniae to the bloodstream. However, the delivery of higher doses of Ad5mT NF (5 x 10(8) PFU) was not beneficial and in fact the intratracheal adminis tration of a similar dose of control vector (Ad5LacZ) actually enhanced Kle bsiella-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 mur ine Klebsiella pneumonia.