Small-For-Size Liver Transplantation Increases Pulmonary Injury in Rats: Prevention by NIM811

Abstract

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.

Novel mitochondrial transition pore inhibitor N‐methyl‐4‐isoleucine cyclosporin is a new therapeutic option in acute pancreatitis

“…) and pulmonary injury during liver transplantation (Liu et al . ). Importantly, none of the studies reported side‐effects.…”

Anti-inflammatory Effects of Extracellular Cyclosporins Are Exclusively Mediated by CD147

“…3,4,6 NIM811, a nonimmunosuppressive derivative of the immunosuppressive drug cyclosporine A (CsA), which retains the high affinity of CsA to the CD147 binding site of CypA, has been shown to diminish neutrophil infiltration into lung tissues. 7 However, administration of NIM811 fails to distinguish between intra-and extracellular signaling pathways due to its cell permeability. In contrast, the multifunctionality of the high molecular weight CsA derivative MM218, which does not enter the cytoplasm, makes a clear correlation between the inhibition of eCyp-CD147-mediated signaling and the attenuation of induced lung inflammation difficult.…”

Suppression of Graft Regeneration, Not Ischemia/Reperfusion Injury, Is the Primary Cause of Small-for-Size Syndrome after Partial Liver Transplantation in Mice

“…Complex pathogenic aspects are involved, including pre-existing liver disease, latent disease (steatosis, ethanol injury), regeneration, vascular inflow (portal hyperperfusion, arterial hypoperfusion), age, health status, cirrhosis, anatomic variations in vascular structure, warm/cold ischemia and vascular reconstruction [7] , [23] , [24] . Among these factors, suppression of liver regeneration and increased graft injury and necrosis have been shown to be closely associated with small-for-size graft failure [2] , [12] , [13] , [18] , [23] , [25] .…”

“…The widespread application of liver transplantation for end-stage liver diseases, a shortage of deceased donors and advancements in modern techniques of hepatectomy have made living donor liver transplantation (LDLT) a routine procedure [1] . Moreover, based on the regeneration potential of hepatocytes, the use of partial liver transplantation has increased rapidly in recent years, and has dramatically alleviated mortality on the waiting list [2] . The application of smaller grafts would be a revolution in transplantation, however, in clinical practice, a major concern is the adequacy of recipient graft volume while retaining a sufficient remnant liver volume within the donor [3] .…”