Objective: To investigate the local secretion of tumor necrosis factor
(TNF) in the lung as a source for systemic TNF. Design: Prospective,
randomized experimental trials. Setting: Laboratory. Subjects: Hartley
guinea pigs. Interventions: Female guinea pigs were challenged intrat
racheally with 10(3) to 10(9) Escherichia coli. Two and eight hrs afte
r the bacterial challenge, colony-forming units of bacteria in the lun
g and blood, TNF and prostaglandin E(2) (PGE(2)) in the bronchoalveola
r lavage fluid, and serum TNF concentrations were determined. At the s
ame time, alveolar macrophages were harvested and cultured in vitro, a
nd TNF and PGE(2) secretions were measured. Measurements and Main Resu
lts: TNF and PGE(2) concentrations were either not detected in broncho
alveolar lavage fluid or were found in very low levels in control anim
als. High concentrations of TNF and PGE(2), however, were found in bac
teria-challenged animals. Two hours after inoculation of bacteria, TNF
in the bronchoalveolar lavage fluid had a significant correlation wit
h TNF values in the serum. The TNF concentration in aortic blood was s
ignificantly higher than TNF concentration in right atrial blood. For
comparable inocula, TNF in the bronchoalveolar lavage fluid after 8 hr
s was significantly lower than at 2 hrs, but PGE(2) levels remained hi
gh. Lipopolysaccharide-stimulated alveolar macrophage secretion of TNF
in vitro was depressed in animals with high PGE(2) levels in bronchoa
lveolar lavage fluid and high numbers of viable bacteria in the lungs.
Conclusions: During pulmonary Gram-negative infection, the lungs may
be a major source of TNF in the blood. The magnitude of TNF secretion
by the lungs is highly dependent on the intensity of infection during
its early stages. By 8 hrs after onset of infection, TNF secretion app
ears to downregulate, possibly by endogenous PGE(2).