This study investigated whether amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), improves liver regeneration after small-for-size liver transplantation. Livers of male C57BL/6 mice were reduced to ~50% and ~30% of original sizes and transplanted. After transplantation, AR and AR mRNA increased in 50%- but not in 30%-grafts. 5-Bromodeoxyuridine (BrdU) labeling, proliferating cell nuclear antigen (PCNA) expression, and mitotic index increased substantially in 50%- but not 30%-grafts. Hyperbilirubinemia and hypoalbuminemia occurred and survival decreased after transplantation of 30%- but not 50%-grafts. AR neutralizing antibody blunted regeneration in 50%-grafts whereas AR injection (5 μg/mouse, iv) stimulated liver regeneration, improved liver function and increased survival after transplantation of 30%-grafts. Phosphorylation of EGFR and its downstream signaling molecules Akt, mTOR, p70S6K, ERK and JNK increased markedly in 50%- but not 30%-grafts. AR stimulated EGFR phosphorylation and its downstream signaling pathways. EGFR inhibitor PD153035 suppressed regeneration of 50%-grafts and largely abrogated stimulation of regeneration of 30%-grafts by AR. AR also increased cyclin D1 and cyclin E expression in 30%-grafts. Together, liver regeneration is suppressed in small-for-size grafts, as least in part, due to decreased AR formation. AR supplementation could be a promising therapy to stimulate regeneration of partial liver grafts.

For most biliary cancers, the stricture is high enough to allow the placement of a stent fully above the papilla, but this is not possible for most pancreatic cancers (or any papillary cancers). An "inside-stent" approach would be possible in about one-third of patients with malignant obstructive jaundice if a clearance length of over 2 cm between the stricture and the sphincter is required, and in about 45% of patients if a minimum clearance of 1 cm is required. A 30-40 degrees flexion in the distal part of the stent would approximate the average angulation in the axis of the common bile duct and help to prevent dislocation.

Pulmonary complications after liver transplantation (LT) often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LTassociated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 μM) for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG) and quartersize grafts (QSG), respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5-18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1β mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-forsize LT.

No abstract