The pattern of lung injury induced after pulmonary exposure to tumor necrosis factor-alpha depends on the route of administration.
TNF-alpha is a protein elaborated by monocytes and macrophages in response to endotoxin. The in vivo consequences of TNF-alpha elaboration have been examined extensively after intravenous administration of TNF-alpha. Substantially less is known about the effects of TNF-alpha that may be generated locally by resident tissue phagocytes. We investigated the direct effects of TNF-alpha on lung tissue by administering large amounts of human TNF-alpha directly to the lung, either as an aerosol or as an intratracheal bolus. Rats were exposed to an aerosol containing several concentrations of TNF-alpha, resulting in retention of significant quantities of TNF-alpha. The histologic response to inhaled TNF-alpha was characterized by adherence of leukocytes to venular endothelium, endothelial cell disruption, and bronchovascular edema. After aerosol administration, however, there was no evidence of alveolar inflammation or edema. In contrast, intravenous administration of large amounts of human TNF-alpha, at a dose that produced a lung content of TNF-alpha similar to that produced after high-concentration aerosol exposure, resulted in severe alveolar injury and edema. Intravenous administration of TNF-alpha did not result in the bronchovascular changes seen after inhalation. To ensure that sufficient quantities of TNF-alpha were being delivered to the lung, TNF-alpha was given as an intratracheal bolus to rats. This led to measurable absorption, but the spectrum and severity of lung injury was similar to the group that received TNF-alpha as an aerosol. We conclude that in rats, the pulmonary response to the injurious effects of TNF-alpha differ, depending on whether the TNF-alpha is delivered to the air or blood side of the alveolar capillary barrier.
Fuchs
H J
HJ
Department of Pharmacological Sciences, Genentech, Inc., South San Francisco, CA.
Debs
R
R
Patton
J S
JS
Liggitt
H D
HD
D000042:Absorption; D000336:Aerosols; D000818:Animals; D005260:Female; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
D000336:Aerosols; D014409:Tumor Necrosis Factor-alpha