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Research Article

Mediators Released from LPS-challenged Lungs Induce Inflammatory Responses In Liver Vascular Endothelial Cells and Neutrophilic Leukocytes

¹Lawson Health Research Institute ²St. Joseph's Health Center

Submitted 14 July 2009 ; revision received 8 September 2009 ; accepted in final form 5 October 2009

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; 0.5 mg/ml) followed by mechanical ventilation using the isolated perfused mouse lung (IPML) 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/chemokines into the perfusate (Luminex assay) as compared to the saline-controls. Subsequently, primary mouse liver vascular endothelial cells (LVEC) or mouse PMN in vitro were stimulated with the perfusate obtained from saline- or LPS-challenged lungs and assessed for various inflammation-relevant endpoints. The obtained results indicate that stimulation of LVEC with perfusate obtained from LPS-challenged lungs results in 1) ROS production, 2) activation of NFB , 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 up-regulation 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 pro-adhesive phenotype (i.e. E-selectin and ICAM-1 expression) in LVEC, while targeted inhibition (immunoneutralization) of TNF- and/or IL-6 in LPS-lung perfusate had no effect. Taken together, these findings indicate that multiple pro-inflammatory 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.

Acute lung injury; Pulmonary inflammation; Systemic inflammation; Perfused mouse lung