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.
Highlights
We examined the intrinsic hepatic innervation after partial hepatectomy (PH) in rats and the presence and pattern of neural sprouting in regenerating liver
PGP9.5-positive nerve fibers were detected during the entire study period, with alterations in their density and number of positive portal tracts (PTs) (Figure 1A)
At postoperative days (PODs) 1, the percentage of PGP9.5positive PTs was decreased to 46.42% (44.67 +/− 12.98) from 58.62% (59.00 +/− 7.26) in the control group (p > 0.05) and gradually increased to 56.33% (56.14 +/− 7.358) at 6 months post-PH
Summary
We examined the intrinsic hepatic innervation after partial hepatectomy (PH) in rats and the presence and pattern of neural sprouting in regenerating liver. Hepatic re-innervation after experimental orthotopic liver transplantation (OLT) has been studied in the past using immunohistochemistry with antibodies to protein gene product 9.5 (PGP 9.5) and growth-associated protein (GAP-43) in rat models [10,11]. PGP9.5 belongs to the ubiquitin carboxy-terminal hydrolases [12]. It is expressed in neurons and neuroendocrine cells of vertebrates, and is present within the axoplasm of both peripheral and central nerve fibers, rendering it an excellent marker for nerve axons [13]. Its expression is related to axonal growth during neuronal development and regeneration and, GAP-43 is a useful marker for developing or regenerating nerve axons [14,15,16]
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