Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

Abstract

Nonspecific inflammatory response is the major cause for failure of islet grafts at the early phase of intraportal islet transplantation (IPIT). Bilirubin, a natural product of heme catabolism, has displayed anti-oxidative and anti-inflammatory activities. The present study has demonstrated that bilirubin protected islet grafts by inhibiting nonspecific inflammatory response in a syngeneic rat model of IPIT. The inflammation-induced cell injury was mimicked by exposing cultured rat insulinoma INS-1 cells to cytokines (IL-1β, TNF-α and IFN-γ) in in vitro assays. At appropriate lower concentrations, bilirubin significantly attenuated the reduced cell viability and enhanced cell apoptosis induced by cytokines, and protected the insulin secretory function of INS-1 cells. Diabetic inbred male Lewis rats induced by streptozotocin underwent IPIT at different islet equivalents (IEQs) (optimal dose of 1000, and suboptimal doses of 750 or 500), and bilirubin was administered to the recipients every 12 h, starting from one day before transplantation until 5 days after transplantation. Administration of bilirubin improved glucose control and enhanced glucose tolerance in diabetic recipients, and reduced the serum levels of inflammatory mediators including IL-1β, TNF-α, soluble intercellular adhesion molecule 1, monocyte chemoattractant protein-1 and NO, and inhibited the infiltration of Kupffer cells into the islet grafts, and restored insulin-producing ability of transplanted islets.

PEGylated bilirubin nanoparticle as an anti-oxidative and anti-inflammatory demulcent in pancreatic islet xenotransplantation

“…Islet viability was significantly decreased at concentrations of bilirubin higher than 60 mM. This result corresponded with previous reports that pretreatment with 20 mM bilirubin protected insulinoma INS-1 cells from cytokines (IL-1b, TNF-a, and IFN-g), whereas a high bilirubin concentration (50 mM) did not show any protective effect and even reduced cell viability compared to untreated control groups [35]. These data demonstrated that bilirubin had a narrow therapeutic index with respect to dosage.…”

“…The SI values of the two treatment groups were not significantly different from that of the control group (2.02 ± 0.11). These data were in agreement with previously reported data from Zhu, who found that a low concentration (20 mM) of bilirubin did not affect the insulin secretion function of insulinoma INS-1 cells [35]. In addition, pretreatment with bilirubin improved islet function against oxidative injury by reducing lipid peroxidation during the isolation and purification processes [34].…”

“…Exogenous bilirubin supplementation may accumulate in undesired tissues, resulting in jaundice and neurologic damage [38e40]. In addition, the high dose administration of bilirubin reduced cell viability and damaged the insulin secretory function of rat insulinoma INS-1 cells [35]. This indicates a relatively narrow therapeutic index, which makes bilirubin much harder to apply in the clinical setting.…”

Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke-induced emphysema

“…Longterm bilirubin interventions also diminished neutrophil and monocyte-macrophage infiltration, reduced pro-inflammatory cytokine levels and inhibited pulmonary pathology. Additionally, bilirubin has been demonstrated to protect grafts from nonspecific inflammation-induced injury by inhibiting the production of inflammatory mediators and infiltration of Kupffer cells in a rat syngeneic intraportal islet transplantation model [17]. We also found that smoking reduced bilirubin levels, particularly indirect bilirubin, and long-term bilirubin interventions attenuated smokeinduced inflammation and oxidative damage in vivo.…”

Functional improvement of porcine neonatal pancreatic cell clustersviaconformal encapsulation using an air-driven encapsulator

“…Moreover, the small capsules successfully demonstrated selective permeability, which includes the blockage of immune cells and penetration of insulin and glucose. Further studies regarding in vivo biocompatibility, glucose control and protection of islet cells in vivo using antioxidants or anti-inflammatory drugs (Zhu et al, 2010) should be conducted to provide a useful tool for treating diabetes mellitus patients.…”