Endotoxin-induced translocation of interleukin-6 from lungs to the systemic circulation.
It is widely postulated that systemic inflammation related to lung infections is largely caused by cytokine translocation from the lungs into the systemic circulation but there is a paucity of animal models to evaluate this hypothesis. In this proof-of-concept study, we developed a murine model to determine whether interleukin (IL)-6, a primary inflammatory cytokine, translocates following airway exposure to endotoxin. We collected central venous blood from the right atrium and arterial blood from the aorta simultaneously at 4 h and 24 h following intratracheal exposure to endotoxin (25 microg) and measured IL-6 in the serum and broncho-alveolar lavage (BAL) fluid (n = 33 mice). We repeated the experiment following 3 d of treatment with dexamethasone (n = 31 mice). Without stimulation, there was no significant arteriovenous gradient (3 pg/ml with interquartile range [IQR] of 3-5 pg/ml in arterial versus 18 pg/ml with IQR of 8-24 pg/ml in venous serum; P = 0.86). A significant arteriovenous difference was observed by 4 h post-exposure to endotoxin (2813 pg/ml with IQR of 1578-4316 pg/ml in arterial versus 1282 pg/ml with IQR of 778-2699 pg/ml in venous serum; P50.0001). The rise in the BAL IL-6 levels correlated with the increases in the arterial serum levels (P50.0001). Administration of intraperitoneal dexamethasone for 3 d attenuated the increased arteriovenous gradient. This murine model facilitates the estimation of cytokine translocation across the lungs and evaluation of compounds to modulate this gradient.
Tamagawa
Eiji
E
Division of Respiratory Medicine, The University of British Columbia, the Providence Heart and Lung Institute and The James Hogg iCapture Center for Cardiovascular and Pulmonary Research (St Paul's Hospital), Vancouver, BC, Canada.
Suda
Koichi
K
Wei
Yuan
Y
Xing
Li
L
Mui
Tammy
T
Li
Yuexin
Y
van Eeden
Stephan F
SF
Man
S F Paul
SF
Sin
Don D
DD
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001775:Blood Circulation / Q000187:drug effects / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D004731:Endotoxins / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood* / Q000276:immunology / Q000378:metabolism*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D015850:Interleukin-6; D003907:Dexamethasone