49 to 2 47% (p = 0 002) and for segments II, III and IV from 1 24

49 to 2.47% (p = 0.002) and for segments II, III and IV from 1.24 to 1.52% (not significant) (Table S1, Additional file 1 and Fig. 2). Figure 2 Liver/body weight ratio (%) by segments before and after 3 weeks of aortoportal shunting of segments II, III and IV. The total liver weight increases over three weeks, the increase occurring in the non-LGX818 molecular weight shunted segments (I, V, VI, VII and VIII). Macroscopically, a sharp line of demarcation between the shunted and portally perfused sides of the liver was seen on the organ surface

(in vivo) upon relaparatomy at t = three weeks (Fig. 3a). This line corresponded to the transitional zone between segments IV (perfused by the shunt) and V/VIII (perfused by the portal vein). Furthermore, we observed that the liver lobuli had become larger on the portally perfused side. Figure 3 Macro-and microscopic changes after three weeks of shunting. a) Close-up photograph of the transition zone between shunted and portally perfused in-vivo

PI3K inhibitor Tariquidar liver after three weeks. The shunted side exhibits smaller condensed lobuli and a brighter (hyperoxygenized) color, while the portally perfused side exhibits larger lobuli, b) HE stained section of the transition zone showing more condensed lobuli on the shunted side and larger lobuli with dilated portal venules and central veins on the portally perfused side, c) sections from areas perfused by the portal vein and by the shunt showing an even distribution of Ki67 positive cells (control sections of sham buy Idelalisib and baseline livers all show a lower density of Ki67 positive cells). Microscopic changes On microscopic examination with HE staining (of biopsies taken from the chronic experiments), the lobuli on the shunted arterialized side exhibited condensed, smaller liver lobuli. However, reticulin staining revealed no increase in connective tissue deposition between portal triads. Furthermore, no apparent bile duct hyperplasia could be seen or overt signs of damage due to hyperperfusion. On the portally perfused side, the lobuli were expanded, the hepatocytes larger (increased cytoplasm), and the sinusoids, portal venules as well as the central veins were dilated. There were no differences in

the density of Ki67 positive cells or Phosphohistone H3 positive cells between the two sides (Fig. 3b, c). Control sections from sham animals and at baseline before shunting revealed uniformly less Ki67 positive cells in the liver lobuli, tentatively reflecting the pre-interventional normal state. Biochemical/cytokine analyses (acute experiments) There were no statistically significant changes in the concentration of ALAT, ASAT, GT, BIL or ALP at any time nor were there any differences in trends between shunt and sham groups. Serum IL-1 concentration increased slightly but remained statistically unchanged in the sham experiments. In the shunt experiments, IL-1 concentration reached a peak value (63 ± 93 pmol/l) at t = 4 hours after shunt opening (p = 0.009).

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