title: Lung-derived mediators induce cytokine production in downstream organs via an NF-κB-dependent mechanism.
abstract: In the setting of acute lung injury, levels of circulating inflammatory mediators have been correlated with adverse outcomes. Previous studies have demonstrated that injured, mechanically ventilated lungs represent the origin of the host inflammatory response; however, mechanisms which perpetuate systemic inflammation remain uncharacterized. We hypothesized that lung-derived mediators generated by mechanical ventilation (MV) are amplified by peripheral organs in a "feed forward" mechanism of systemic inflammation. Herein, lung-derived mediators were collected from 129X1/SVJ mice after 2 hours of MV while connected to the isolated perfused mouse lung model setup. Exposure of liver endothelial cells to lung-derived mediators resulted in a significant increase in G-CSF, IL-6, CXCL-1, CXCL-2, and MCP-1 production compared to noncirculated control perfusate media (P < 0.05). Furthermore, inhibition of the NF-κB pathway significantly mitigated this response. Changes in gene transcription were confirmed using qPCR for IL-6, CXCL-1, and CXCL-2. Additionally, liver tissue obtained from mice subjected to 2 hours of in vivo MV demonstrated significant increases in hepatic gene transcription of IL-6, CXCL-1, and CXCL-2 compared to nonventilated controls. Collectively, this data demonstrates that lung-derived mediators, generated in the setting of MV, are amplified by downstream organs in a feed forward mechanism of systemic inflammation.
authors.affiliation: Lawson Health Research Institute, London, ON, Canada N6A 4V2.
authors.forename: E K
authors.initials: EK
authors.lastname: Patterson
authors.forename: L J
authors.initials: LJ
authors.lastname: Yao
authors.forename: N
authors.initials: N
authors.lastname: Ramic
authors.forename: J F
authors.initials: JF
authors.lastname: Lewis
authors.forename: G
authors.initials: G
authors.lastname: Cepinskas
authors.forename: L
authors.initials: L
authors.lastname: McCaig
authors.forename: R A W
authors.initials: RA
authors.lastname: Veldhuizen
authors.forename: C M
authors.initials: CM
authors.lastname: Yamashita
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016179:Granulocyte Colony-Stimulating Factor; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D012121:Respiration, Artificial / Q000009:adverse effects
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D016179:Granulocyte Colony-Stimulating Factor