EXOGENOUS RH-UROKINASE MODIFIES INFLAMMATION AND PSEUDOMONAS-AERUGINOSA INFECTION IN A RAT CHRONIC PULMONARY INFECTION MODEL

The effect of recombinant human urokinase (rh-UK) in a rat model of ch ronic Pseudomonas aeruginosa pulmonary infection was studied. Efficacy was assessed by lung histology and quantitative bacteriology. Male Sp rague-Dawley rats received 1 x 10(4) or 1 x 10(5) P. aeruginosa encaps ulated in agar beads via the intratracheal route on day 1. Intratrache al administration of up to 12 500 units of rh-UK on day 21 led to a do se-dependent disappearance of viable organisms from the lungs by day 2 4 in rats receiving 10(4) organisms. In slightly longer term infection s (30 days), rh-UK was still effective in facilitating the disappearan ce of the organisms from the lungs of most of the treated animals. rh- UK was effective in eliminating organisms when animals were infected w ith 10(4), but not 10(5) bacteria. In vitro analysis revealed that rh- UK was not directly toxic for the organisms. Histologically, lungs fro m short-term infected control animals exhibited acute inflammation, in flammatory cell infiltrates, and fibrin deposition. Histology of lungs from UK-treated, short-term infected rats revealed decreased airway i nflammation and cellular infiltration compared with infected controls. Lungs from infected animals treated with 12 500 units of rh-UK were h istologically indistinguishable from the lungs of uninfected control a nimals, except for the foreign body reaction. These results indicate t hat exogenous rh-UK may be efficacious in the treatment of pulmonary i nflammation accompanying exposure to Gramnegative bacteria such as P. aeruginosa.