Endotoxin-induced acute lung injury requires interaction with the liver

• Published in: American journal of physiology. Lung cellular and molecular physiology 2005-11, Vol.289 (5), p.L769-L776
• Main Authors: Siore, Amsel M, Parker, Richard E, Stecenko, Arlene A, Cuppels, Chris, McKean, Martha, Christman, Brian W, Cruz-Gervis, Roberto, Brigham, Kenneth L
• Format: Article
• Language: English
• Subjects: Animals; Body Water - drug effects; Body Water - metabolism; Cytokines - metabolism; Disease Models, Animal; Endotoxins - toxicity; Humans; Isoprostanes - metabolism; Leukocyte Count; Liver - drug effects; Liver - physiopathology; NF-kappa B - metabolism; Oxidative Stress - drug effects; Perfusion; Pulmonary Circulation - drug effects; Respiratory Distress Syndrome, Adult - etiology; Respiratory Distress Syndrome, Adult - physiopathology; Sus scrofa; Vascular Resistance - drug effects
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00137.2005

1 Center for Translational Research in the Lungs, McKelvey Center for Lung Transplantation, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and 2 Vanderbilt University School of Medicine, Nashville, Tennessee Submitted 24 March 2005 ; accepted in final form 2 July 2005 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- , IL-6, and 8-isoprostane (a marker of oxidative stress), and activation of the transcription factor (NF- B) 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- , 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- , IL-6, and 8-isoprostane concentrations, and severe lung edema. NF- B 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. liver-lung interaction; oxidative stress; acute respiratory distress syndrome Address for reprint requests and other correspondence: K. L. Brigham, Center for Translational Research in the Lungs, Whitehead Biomedical Research Bldg., Emory Univ. School of Medicine, 615 Michael St., Ste. 205, Atlanta, GA 30322 (e-mail: kbrigha{at}emory.edu )