Intrapulmonary TNF gene therapy reverses sepsis-induced suppression of lung antibacterial host defense

Sepsis syndrome is frequently complicated by the development of nosocomial infections, particularly Gram-negative pneumonia, Although TNF-alpha (TNF) has been shown to mediate many of the pathophysiologic events in sepsis, th is cytokine is a critical component of innate immune response within the lu ng, Therefore, we hypothesized that the transient transgenic expression of TNF within the lung during the postseptic period could augment host immunit y against nosocomial pathogens. To test this, mice underwent 26-gauge cecal ligation and puncture (CLP) as a model of abdominal sepsis, followed 24 h later by intratracheal (i.t.) administration of Pseudomonas aeruginosa. In animals undergoing sham surgery followed by bacterial challenge, Pseudomona s were nearly completely cleared from the lungs by 24 h, In contrast, mice undergoing CLP were unable to clear P. aeruginosa and rapidly developed bac teremia, Alveolar macrophages (AM) recovered from mice 24 h after CLP produ ced significantly less TNF ex vivo, as compared with AM from sham animals. Furthermore, the adenoviral mediated transgenic expression of TNF within th e lung increased survival in CLP animals challenged with Pseudomonas from 2 5% in animals receiving control vector to 91% in animals administered recom binant murine TNF adenoviral vector. Improved survival in recombinant murin e TNF adenoviral vector-treated mice was associated,vith enhanced lung bact erial clearance and proinflammatory cytokine expression, as well as enhance d AM phagocytic activity and cytokine expression when cultured ex vivo. The se observations suggest that intrapulmonary immunostimulation with TNF can reverse sepsis-induced impairment in antibacterial host defense.