Experimental Lung Research, 37, 419–426, 2011 Copyright © Informa Healthcare USA, Inc. ISSN: 0190-2148 print / 1521-0499 online DOI: 10.3109/01902148.2011.583712 The biological effects of lung-derived mediators on the liver Nicole A. Rocca, 1 Melissa G. Walker, 1 Lynda A. McCaig, 2 Li-Juan Yao, 2 Richard F. Potter, 2 Ruud A. W. Veldhuizen, 1 and James F. Lewis 3 1 Department of Physiology and Pharmacology and Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada 2 Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada 3 Department of Medicine and Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada ABSTRACT Despite the use of lung-protective mechanical ventilation (MV), the mortality of patients with acute lung injury remains at 30 to 40%, predominantly due to multiorgan failure. The objective of this study was to determine the biological signiicance of lung-derived mediators on peripheral organ inlammation. The authors utilized an isolated perfused mouse lung model of lipopolysaccharide (LPS)-induced lung inlammation and protective MV to collect lung-derived mediators. Aliquots of perfusate from these animals (or appropriate controls) were then injected intravenously into a cohort of normal animals whose livers were subsequently assessed in vivo using intravital video microscopy. Perfusate from LPS-inlamed lungs contained signiicantly higher concentrations of inlammatory mediators than perfusate from saline-instilled lungs. Assessment of livers in the second cohort of animals 120 minutes after perfusate injection revealed decreased sinusoidal blood low, leukocytosis, and increased cell death in those receiving perfusate from LPS-inlamed lungs compared to perfusate from saline controls. There were no differences between control animals that received pure perfusate or pure LPS mixed with perfusate. These results showed that lung-derived mediators had a signiicant biological effect on non- pulmonary organs within a short period of time after administration. Therapies targeting these mediators may prevent multiorgan failure and death in patients with acute lung injury. KEYWORDS inflammation, intravital microscopy, isolated perfused lung, liver, lung injury, multiple organ failure Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are clinically characterized by hypoxemia, decreased lung compliance, and no evidence of left heart failure [1]. Although simplistic by deinition, its pathophysiology is complex and changes over the course of the dis- ease. Our laboratory and others have shown that the pulmonary inlammatory response signiicantly con- tributes not only to the lung dysfunction in these patients, but also to the development of multiorgan failure (MOF) and death [2–6]. Received 12 November 2010; accepted 20 April 2011. These studies were supported by a grant from the Canadian Institute of Health Research (grant number 165252). Address correspondence to James F. Lewis, Lawson Health Research Institute F4-117, 268 Grosvenor Street, London, ON, Canada, N6A 4V2. E-mail: jlewis@uwo.ca Mechanical ventilation (MV) is the only interven- tion that has consistently been shown to improve the outcome of patients with ALI, although even with more protective modes of MV currently im- plemented, mortality rates remain at 30 to 40%. Indeed, a recent systemic review of almost 5000 stud- ies conducted between 1994 and 2006 reported a pooled mortality of 44% for observational studies and 36% for randomized controlled trials [7]. In- terestingly, most patients with ALI ultimately die of MOF rather than respiratory failure, and there is evi- dence that MV represents an important link between the initial pulmonary inlammatory response and the development of the systemic inlammatory response syndrome (SIRS) and MOF [8, 9]. For example, the same markers of inlammation observed in the bron- choalveolar lavage (BAL) of patients with ALI were also found to be elevated in serum [4]. However, there 419 Exp Lung Res Downloaded from informahealthcare.com by University of Western Ontario on 12/19/12 For personal use only.