Liver regeneration: immunohistochemichal study of intrinsic hepatic innervation after partial hepatectomy in rats

Abstract

BackgroundWe examined the intrinsic hepatic innervation after partial hepatectomy (PH) in rats and the presence and pattern of neural sprouting in regenerating liver.MethodsMale Wistar rats (age 9–13 weeks-w, weight 204-356 g), were submitted to two-thirds PH. Rats were sacrificed at postoperative days (d) 1, 3, 5, 7, at 2 and 4 w, and at 3 and 6 months (m) (6–7 animals/group, control group n = 4). Immunohistochemistry for the pan-neural marker protein gene product 9.5 (PGP9.5) and growth-associated protein 43 (GAP-43), a marker of regenerating nerve axons, was performed on tissue sections from the R1 lobe of the regenerating liver. Portal tracts (PTs) with immunoreactive fibers were counted in each section and computer-assisted morphometric analysis (Image Pro Plus) was used to measure nerve fiber density (number of immuno-positive nerve fibers/mm2 (40x)).ResultsImmunoreactivity for PGP9.5 was positive in all groups. The number of PGP9.5 (+) nerve fibers decreased from 0.32 +/− 0.12 (control group) to 0.18 +/− 0.09 (1d post-PH group), and gradually increased reaching pre-PH levels at 6 m (0.3 +/− 0.01). In contrast, immunoreactivity for GAP-43 was observed at 5d post-PH, and GAP-43 (+) PTs percentage increased thereafter with a peak at 3 m post-PH. GAP-43 (+) nerve fiber density increased gradually from 5d (0.05 +/− 0.06) with a peak at 3 m post-PH (0.21 +/− 0.027). At 6 m post-PH, immunoreactivity for GAP-43 was not detectable.ConclusionsFollowing PH in rats: 1) nerve fiber density in portal tracts decreases temporarily, and 2) neural sprouting in the regenerating liver lobes starts at 5d, reaches peak levels at 3 m and disappears at 6 m post-PH, indicating that the increase in hepatic mass after PH provides an adequate stimulus for the sprouting process.

Silymarin Accelerates Liver Regeneration after Partial Hepatectomy

“…The liver is one of the most complex organs, playing an important role in digestion, detoxification, blood sugar regulation, and fat metabolism. Liver regeneration induced by surgical injury is an orchestrated response [ 24 – 26 ]. Silymarin is currently the world's most effective treatment for liver disease.…”

Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis

“…Similarly, liver regeneration was also diminished in TrkA Avil −/− mice with or without injection of SW033291. It is documented that sensory and sympathetic nerves are both innervated in the liver 44 , and active neural sprouting was observed after partial hepatectomy, suggesting an essential role of sensory nerves in liver regeneration 45 . However, we observed liver regeneration rate was not altered in the EP4 Avil −/− mice in compare with their wild type littermates, neither does SW033291 treatment show any difference between these two groups, indicating that sensory nerve is indispensable in liver regeneration, but the mechanism is not through PGE2-EP4 signaling on sensory nerves.…”

Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration

“…However considering the results of Iatropoulos[ 46 ] and Kandilis et al [ 27 ], it should be assumed that the possibility of creating new lobules (lobule proliferation) cannot be completely excluded. Doubt is reinforced by the fact that on the corrosion cast of the regenerated liver we have observed the lobules, which are smaller than the sizes of the liver lobules of the CG animals.…”

“…A literature review suggests that most of the authors confirm the proliferation of hepatocytes following the PH[ 6 , 7 , 14 , 22 - 24 ]. Some authors highlight the hypertrophy of the hepatocytes[ 25 - 27 ] and/or the simultaneous presence of both processes[ 13 , 28 ].…”

“…The issue whether the size of the liver lobule is being increased (which would happen in the case of increasing the number of existing hepatocytes as well as their hypertrophy)[ 25 , 26 , 29 ] or there are developed new lobules, even with unusual architectonics[ 27 ], or both processes are occurring, remains unsolved.…”