Evidence of nitric oxide being the initial trigger of the liver regeneration cascade

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Wang, Hui Helen
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Liver regeneration is a cascade of events (elevation of growth factors, cytokines and hormones, and early gene expression) leading to rapid hepatocyte proliferation to restore its lost cell mass in response to partial hepatectomy (PHX) or cell injury. The initial trigger for the cascade is still unidentified despite intensive research started over a century ago. The hypotheses of the project comprise: (1) the hemodynamic change ($\uparrow$ blood flow/liver mass ratio) occurring immediately upon PHX serves as the initial trigger; (2) this ratio change alters the concentration of flow-dependent factor(s) leading to production of proliferative factors (PF, which represents a combination of growth factors, cytokines and hormones) that represent the onset of the regeneration cascade. Experimentally, a 2/3 PHX rat model, an in vitro hepatocyte bioassay measuring the PF production in the plasma and an in vivo method directly measuring liver regeneration by liver weight were utilized. This approach was combined with the pharmacological manipulation of flow-dependent factors (adenosine, nitric oxide and prostaglandins) to assess their effects on the PF production and liver weight regeneration, in order to test their roles in the initiation of the regenerative response. Selective portal vein branch ligation (PVL), an analogous hemodynamic model to PHX, was also used to test the hypotheses. PVL results in shunting of portal flow to 1/3 of the liver thus causing a similar flow/mass-ratio change as produced by 2/3 PHX. The optimized bioassay results showed a nearly and transient increase of PF in the PHX rat plasma (1-4 hr, peaking at 4 hr after PHX), which is closely related to regeneration and can indicate the initiation of the cascade. The developed bioassay can quantitatively distinguish the PF levels in 1/3 and 2/3 PHX rat plasma. A flow-dependent factor, nitric oxide, was demonstrated to be a key triggering factor for the regeneration cascade and prostaglandins are also involved in the initiation, possibly as a mediator mechanism for the nitric oxide effects. PF is also detected in the PVL rat plasma, indicating a similar initiation to the PHX model. In conclusion, data support the hypotheses of increased blood flow/liver mass upon PHX resulting in increased shear-stress and release of flow-dependent factors, which then lead to the PF production and onset of the liver regeneration.