title: Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes.
abstract: The systemic inflammatory response plays an important role in the progression of acute lung injury (ALI) to multiple organ dysfunction syndrome (MODS). However, the role of lung-derived inflammatory mediators in induction of the inflammatory response in remote organs is poorly understood. To address the above, we investigated the effects of lung inflammation on induction of inflammatory response(s) in the liver in vitro. Inflammation in mouse lungs was induced by intranasal administration of lipopolysaccharide (LPS; 1 mg/ml) followed by mechanical ventilation using the isolated perfused mouse lung method to obtain and characterize lung perfusate from the pulmonary circulation. LPS administration to mouse lungs resulted in an increased release of inflammation-relevant cytokines and chemokines into the perfusate (Luminex assay) compared with the saline-controls. Subsequently, primary mouse liver vascular endothelial cells (LVEC) or mouse polymorphonuclear leukocytes (PMN) in vitro were stimulated with the perfusate obtained from saline- or LPS-challenged lungs and assessed for various inflammation-relevant end points. The obtained results indicate that stimulation of LVEC with perfusate obtained from LPS-challenged lungs results in 1) reactive oxygen species (ROS) production; 2) activation of NF-kappaB; and 3) expression of E-selectin, ICAM-1, and VCAM-1 and a subsequent increase in PMN rolling and adhesion to LVEC. In addition, perfusate from LPS-challenged lung induced activation of PMN with respect to increased ROS production and upregulation of cell surface levels of adhesion molecules MAC-1 and VLA-4. Heat-inactivation of the perfusate obtained from LPS-challenged lungs was very effective in suppressing increased proadhesive phenotype (i.e., E-selectin and ICAM-1 expression) in LVEC, whereas targeted inhibition (immunoneutralization) of TNF-alpha and/or IL-6 in LPS-lung perfusate had no effect. Taken together, these findings indicate that multiple proinflammatory mediators (proteinaceous in nature) released from inflamed lungs act synergistically to induce systemic activation of circulating PMN and promote inflammatory responses in liver vascular endothelial cells.
authors.affiliation: Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Markovic
authors.forename: L A
authors.initials: LA
authors.lastname: McCaig
authors.forename: J
authors.initials: J
authors.lastname: Stephen
authors.forename: S
authors.initials: S
authors.lastname: Mizuguchi
authors.forename: R A W
authors.initials: RA
authors.lastname: Veldhuizen
authors.forename: J F
authors.initials: JF
authors.lastname: Lewis
authors.forename: G
authors.initials: G
authors.lastname: Cepinskas
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology*; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology*; D006505:Hepatitis / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036904:Leukocyte Rolling; D008070:Lipopolysaccharides; D008099:Liver / Q000098:blood supply / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D012121:Respiration, Artificial; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D019040:E-Selectin; D018836:Inflammation Mediators; D039041:Integrin alpha4beta1; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C433788:lipopolysaccharide, E. coli O26-B6; D018799:Intercellular Adhesion Molecule-1; D019255:NADPH Oxidases