The systemic and pulmonary LPS binding protein response to intratracheal lipopolysaccharide.
LPS binding protein (LBP) is an acute-phase glycoprotein that facilitates LPS activation of immune cells through interactions with CD14 and Toll-like receptor 4. Initially, LBP production was thought to occur exclusively in the liver in response to stimulation with TNF-alpha, IL-1, and IL-6. More recently, it has been shown that type II pneumocytes are also capable of LBP production. Little is known, however, regarding the regulation and or distribution of this protein in response to localized intrapulmonary infection. We performed time-course experiments challenging C3H mice intratracheally with LPS (10 mug). In separate experiments, mice deficient in IL-6 were given the same dose of intratracheal LPS and euthanized 8 h later. Despite the intratracheal route of LPS administration, an increase in plasma LBP concentrations occurred earlier and was of greater magnitude than the increase observed in bronchoalveolar lavage fluid. Liver LBP mRNA increased to a greater extent than did lung LBP mRNA. Whereas the TNF-alpha response remained localized within the alveolar space, IL-6 was increased both locally and in plasma. Of several tissues analyzed, the lung was the greatest producer of IL-6 mRNA. Plasma LBP was significantly decreased in the IL-6-deficient mice compared with wild-type controls challenged with intratracheal LPS. We conclude that lung-derived IL-6 is an important mediator of hepatic LBP up-regulation. We speculate that the disruption of these lung-liver signaling pathways may be important to host response efforts to confine infection to the lung. If impaired, this may be one mechanism underlying the increased mortality observed in patients with liver disease who develop pneumonia.
Departments of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Lisa
L
Gamble
Gregory J
GJ
Bagby
Lee J
LJ
Quinton
Kyle I
KI
Happel
Joseph P
JP
Mizgerd
Ping
P
Zhang
Steve
S
Nelson
D000818:Animals; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000737:chemistry; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D011485:Protein Binding; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014132:Trachea / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha