Decreased Pulmonary Vasoreactivity in an Animal Model of ChronicPseudomonasPneumonia

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Abstract
Chronic pulmonary infection/colonization caused by P. aeruginosa accounts formuch of the morbidity and mortality in cystic fibrosis (CF). The effect of chronic pulmonary P. aeruginosa infection on the pulmonary circulation has not been studied. Therefore, we investigated the effect of chronic P. aeruginosa infection on pulmonary hemodynamics in a rat model. Two groups of rats were inoculated with either agar beads containing 1.0 .times. 104 colony-forming units of P. aeruginosa (infected) or an equal volume of sterile beads alone (control). In vivo, pulmonary vasoreactivity measured as the percent change in total pulmonary resistance during hypoxia was decreased at 1 wk (22 .+-. 7% versus 57 .+-. 3%), 2 wk (29 .+-. 5% versus 73 .+-. 17%), 3 wk (41 .+-. 8% versus 77 .+-. 14%), and 6 to 9 wk (23 .+-. 10 versus 53 .+-. 7; p < 0.05 all time points; mean .+-. SEM) postinoculation in infected animals when compared with that in time-matched control animals. At 6 to 9 wk postinoculation, pulmonary artery pressure was significantly elevated in infected rats (25.8 .+-. 1.6 versus 21.0 .+-. 1.0 mm Hg; p < 0.05) when compared with that in control animals. Histopathologic findings were characterized by bronchiectasis as well as by chronic bronchial, parenchymal, and perivascular inflammation at all time points in infected animals. The decrease in vasoreactivity was accompanied by significant elevations of 6-keto-PGF1.alpha. and TXB2, but not of LTC4, in lungs of infected animals at 1, 2, 3, and 6 to 9 wk postinoculation when compared with that in time-matched control animals. To further evaluate the relationship between elevation of 6-keto-PGF1.alpha. and decreases in vasoreactivity, separate groups of infected and control animals were studied hemodynamically after the acute administration of the cyclooxygenase inhibitor meclofenamate. This administration restored the pulmonary vascular response to hypoxia (as above) in infected animals (18 .+-. 4% before versus 52 .+-. 12% after meclofenamate, p < 0.05). We conclude that chronic pulmonary infection by P. aeruginosa in the rat is characterized by chronic inflammation, reduced pulmonary vasoreactivity in association with elevated lung levels of 6-keto-PGF1.alpha. and TXB2, and the eventual development of pulmonary hypertension.