Intestinal injury following liver transplantation was mediated by TLR4/NF-κB activation-induced cell apoptosis

Abstract

Intestinal motility and barriers are often impaired due to intestinal congestion during liver transplantation. Intestinal bacteria and enterogenous endotoxins enter into the blood stream or lymphatic system and translocate to other organs, which can result in postoperative multi-organ dysfunction (MODF) and systemic inflammatory reaction syndrome (SIRS) severely affecting patient survival. However, the mechanisms underlying liver transplantation-induced intestinal injury remain unclear and effective therapies are lacking. Thus, the present study investigated whether these effects were associated with endotoxin-mediated apoptosis. Rat autologous orthotopic liver transplantation (AOLT) models were established to observe dynamic intestinal injuries at different time-points following reperfusion. Changes in the levels of endotoxins and the primary receptor, toll-like receptor 4 (TLR4), as well as its downstream signaling molecule, nuclear factor-κB (NF-κB) were all determined. Finally, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were conducted to detect caspase-3 expression and intestinal cell apoptosis, respectively. AOLT resulted in significant pathological intestinal injury, with the most serious intestine damage apparent four or eight hours following reperfusion. Furthermore, the levels of endotoxins and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, peaked during this time period and gradually decreased to the normal level. Notably, TLR4 and downstream NF-κB expression, as well as NF-κB-mediated caspase-3 activation and intestinal cell aapoptosis coincided with the intestinal pathological damage. Thus, the possible mechanism of post-liver transplantation intestinal injury was demonstrated to be associated with NF-κB activation-induced cell apoptosis.

Characterization and evolution of intestine injury at the anhepatic phase in portal hypertensive rats

“…Endotoxins that are over-produced during liver transplantation bind to the primary receptor, toll-like receptor 4, which is important in post-liver transplantation intestinal injury. Yuan et al (35) recently demonstrated that levels of enterogenous endotoxin peaked at 8 h following reperfusion, the point at which the intestine exhibited the most notable damage. However, in the present study, the levels of endotoxin reached their peak at 12 h following reperfusion.…”

Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure

“…Intestinal epithelial cells have been described as a source of IL-6 upon stimulation with proinflammatory cytokines, e.g., TNF-α (14). Finally, it has been shown that TNF-α peaks with maximum intestinal injury frequently occurring upon liver transplantation (15) and also sustains chronic inflammation in IBD. Anti-TNF-α antibodies have become a mainstay in IBD treatment.…”

ROLE OF TRANSCRIPTIONAL FACTOR NF-κB IN DEVELOPMENT OF OXIDATIVE STRESS IN HEART OF RATS DURING SYSTEMIC INFLAMMATORY RESPONSE INDUCED BY BACTERIAL LIPOPOLYSACCHARIDE

“…За даними Yuan D.D. провідну роль у патогенезі ССЗВ відіграє активація ядерного транскрипційного фактору κB (NF-κB) через Toll-подібний рецептор-4 (TLR-4) [5]. Існує п'ять білків у сім'ї NF-κB ссавців: NF-κB1, NF-κB2, RelA, RelB та c-Rel.…”