Innate immune mechanisms in ischemia/reperfusion.

Ischemia/reperfusion (I/R) injury remains a major problem in solid organ transplantation, as it adversely impacts both short and long term outcomes. It has been well established that the innate immune system plays a significant role in the pathogenesis of I/R injury. In contrast, the proximal molecular signaling events that initiate activation of the innate immune system are less clear.

Carbon monoxide decreases the level of iNOS protein and active dimer in IL-1beta-stimulated hepatocytes.

There is evidence that NO can regulate CO production, however less is known about CO regulation of NO synthesis. Our studies were undertaken to define how CO regulates iNOS in cultured hepatocytes. CO (250ppm) exposure resulted in a significant decrease in iNOS protein, nitrite production, level of active iNOS dimer and cytosolic iNOS activity in cells stimulated with cytokines (IL-1beta) or transfected with the human iNOS gene.

HMGB1 preconditioning: therapeutic application for a danger signal?

High mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. In contrast to the proinflammatory role of HMGB1, recent evidence suggests beneficial applications of HMGB1 in injury states. One such application is the use of HMGB1 as a preconditioning stimulus.

Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury.

Endogenous ligands released from damaged cells, so-called damage-associated molecular pattern molecules (DAMPs), activate innate signaling pathways including the TLRs. We have shown that hepatic, warm ischemia and reperfusion (I/R) injury, generating local, noninfectious DAMPs, promotes inflammation, which is largely TLR4-dependent. Here, we demonstrate that increasing dendritic cell (DC) numbers enhance inflammation and organ injury after hepatic I/R.

Linking proximal and downstream signalling events in hepatic ischaemia/reperfusion injury.

Hepatic I/R (ischaemia/reperfusion) injury occurs in a variety of clinical settings including transplantation, elective liver resections and trauma. One of the challenges in studying the pathophysiology of I/R injury is the fact that the liver plays a central role in a variety of metabolic pathways in addition to governing aspects of immune surveillance and tolerance. The pathways activated in response to insults as varied as toxins, microbial and endogenous ligands and I/R may share common elements.