Thrombopoietin limits IL-6 release but fails to attenuate liver injury in two hepatic stress models.
OBJECTIVE
Various pleiotropic substances have been suggested as candidates that directly reduce the severity of liver injury after hepatic ischemia/reperfusion (I/R) and upon acute liver failure (ALF). Herein, we studied whether thrombopoietin (TPO), the main regulator of megakaryopoiesis and thrombopoiesis, showed hepatoprotective effects and might mediate an antiapoptotic function in liver tissue under stress.


RESULTS
In livers with ALF or undergoing warm hepatic I/R, injury was quantified by intravital fluorescence microscopy, chemical, and immunohistochemical analysis as well as western immunoblot. Induction of both ALF and I/R injury led to hepatocellular expression of c-mpl, the receptor of TPO. Exogenous application of recombinant TPO in a low (12.5 microg/kg) as well as a high (75 microg/kg) dose, however, did not ameliorate postischemic perfusion and leukocyte endothelial cell interaction, but slightly aggravated transaminase release upon I/R. Similarly, TPO was unable to dampen hepatic microcirculatory deteriorations after the induction of ALF, but caused an increase of leukocyte accumulation and transaminase activity when applied in high dose. Low dose of TPO did not influence the amount of hepatocellular apoptosis, whereas high-dose TPO slightly diminished the activation of caspase 3. Interestingly, exogenous TPO application completely reversed the stress-induced increase of plasma IL-6 levels, suggesting a negative feedback of TPO on IL-6 release.


CONCLUSIONS
Although the existence of the TPO-receptor on target liver cells TPO plays only a minor role in mediating hepatocyte apoptosis and does not provide protection against hepatic injury, contrasting the efficacy of the related hematopoietic growth factor erythropoietin.
Eipel
Christian
C
Institute for Experimental Surgery, University of Rostock, Rostock, Germany. christian.eipel@uni-rostock.de
Hardenberg
Jost von
Jv
Negendank
Steffen
S
Abshagen
Kerstin
K
Vollmar
Brigitte
B
D000818:Animals; D022781:Hepatocytes / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D013926:Thrombopoietin / Q000378:metabolism* / Q000494:pharmacology
D015850:Interleukin-6; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin