Endotoxin-induced acute lung injury requires interaction with the liver.
Clinical and laboratory data indicate that the liver plays an important role in the incidence, pathogenesis, and outcome of acute lung injury/acute respiratory distress syndrome. To distinguish direct effects of endotoxin on the lungs from liver-dependent effects during the early phase of the response to endotoxemia, we used an in situ perfused piglet preparation in which only the ventilated lung or both the lung and liver could be included in a blood perfused circuit. We monitored pulmonary vascular resistance, oxygenation, neutrophil count, lung edema as reflected by wet-dry weights of lung tissue, perfusate concentrations of TNF-alpha, IL-6, and 8-isoprostane (a marker of oxidative stress), and activation of the transcription factor (NF-kappaB) in lung tissue before and for 2 h after endotoxin. When only the lung was perfused, endotoxin caused pulmonary hypertension and neutropenia; but oxygenation was maintained; TNF-alpha, IL-6, and 8-isoprostane levels were minimally elevated; and there was no lung edema. When both the liver and lung were perfused, endotoxin caused marked hypoxemia, large increases in perfusate TNF-alpha, IL-6, and 8-isoprostane concentrations, and severe lung edema. NF-kappaB activation in the lung was greatest when the liver was in the perfusion circuit. We conclude that the direct effects of endotoxemia on the lungs include vasoconstriction and leukocyte sequestration, but not lung injury. Intense activation of the inflammatory response and oxidative injury that results in pulmonary edema and hypoxemia (acute lung injury) requires interaction of the lungs with the liver.
Siore
Amsel M
AM
Center for Translational Research in the Lungs, Whitehead Biomedical Research Bldg., Emory Univ. School of Medicine, Atlanta, GA 30322, USA.
Parker
Richard E
RE
Stecenko
Arlene A
AA
Cuppels
Chris
C
McKean
Martha
M
Christman
Brian W
BW
Cruz-Gervis
Roberto
R
Brigham
Kenneth L
KL
D000818:Animals; D001834:Body Water / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D028421:Isoprostanes / Q000378:metabolism; D007958:Leukocyte Count; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D011652:Pulmonary Circulation / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000503:physiopathology*; D034421:Sus scrofa; D014655:Vascular Resistance / Q000187:drug effects
D016207:Cytokines; D004731:Endotoxins; D028421:Isoprostanes; D016328:NF-kappa B