Submitted to: Journal of Applied Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/5/2003
Publication Date: 10/1/2003
Citation: Rivera, C.A., Tcharmtchi, M.H., Mendoza, L., Smith, W.C. 2003. Endotoxemia and hepatic injury in a rodent model of hindlimb unloading. Journal of Applied Physiology. 95(4):1656-1663. Interpretive Summary: A component of bacterial cell walls called endotoxin can cause significant liver injury. This has been shown in experiments where endotoxin is injected directly into the blood stream of animals. In this study we found that the stress of hind limb unloading well cause endotoxin to appear in the blood coming from the gastrointestinal track (a site rich in bacteria) and going to the liver. These animals develop significant liver injury with associated inflammation in the liver. The inflammatory process appears very similar to the liver inflammation seen with obesity.
Technical Abstract: Hindlimb unloading (HU) is known to induce physiological alterations in various organ systems that mimic some responses observed following exposure to microgravity. In the present study, the consequence of up to 4 weeks HU on the liver was assessed in male Wistar rats and two mouse strains: endotoxin-sensitive C57BL/6 mice and endotoxin-resistant C3H/HEJ mice. Plasma levels of endotoxin, a known stimulator of hepatic injury, were measured in portal and systemic blood samples. Endotoxin was elevated by approximately 50% in portal blood samples of mice and rats, but was not detectable in systemic blood. This low-grade portal endotoxemia was associated with hepatic injury in rats and C57BL/6 mice as indicated by inflammation and elevated serum transaminase activities. Blood levels of the cytokine TNF-alpha were increased by approximately 50% in C57BL/6 mice; no significant elevation of this cytokine was detected in rats. Messenger RNA levels of the acute phase proteins serum amyloid A, haptoglobin and lipopolysaccaride binding protein were significantly enhanced after 3 weeks of HU in endotoxin-sensitive rodents. In contrast, no histological changes or significant increases in serum enzyme activity were detected following HU in C3H/HEJ mice despite portal endotoxin levels of 222 +/- 83.4 pg/ml. At the 3-week time point, expression of acute phase proteins was not elevated in C3H/HEJ mice; however expression after 4 weeks of HU was similar to endotoxin-sensitive rodents. In conclusion, these findings indicate that HU induced mild portal endotoxemia, which very likely contributes to the observed hepatic injury in endotoxin-sensitive rodents.