The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair

Abstract

The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

“…The increased expression of VEGF could therefore be a response to endothelial barrier disruption or to cellular hypoxia following SOS. In fact, microcirculatory disturbances lead to insufficient energy supply and reduced hepatic tissue oxygenation (46). The increased HIF1a mRNA levels that we detected underline the presence of hepatic hypoxia in SOS and could contribute to VEGF induction.…”

“…Hepatic VEGF mRNA expression is significantly increased in the rat model in parallel with sinusoidal damage (44) and serum VEGF increase correlates with the development of SOS in patients after hematopoietic stem cell transplantation (45). VEGF plays a major role in maintaining SEC differentiation (46)(47)(48). The increased expression of VEGF could therefore be a response to endothelial barrier disruption or to cellular hypoxia following SOS.…”

“…Our molecular observation could partially explain this clinical observation. VEGF blockade by bevacizumab could lead to downregulation of MMP expression by SEC (41,46), and thus attenuate sinusoidal lesions. VEGF-C mRNA was increased in SOS whereas VEGF-A remained at the same level as in controls.…”

New insights into host-pathogen interactions duringEntamoeba histolyticaliver infection

“…Trophozoites of 10-50 µm in diameter with highly versatile morphology cause hindrance in sinusoids (diameter of 5-7 µm; [36]) particularly narrow and tortuous in periportal regions [15]. Obstruction may be reinforced by the recruitment of activated immune cells during the acute inflammatory response [29]. Amoebae may thus exert mechanical forces on the endothelium and the underlying Disse's space and reduce the blood flow, and consequently [7].…”

“…We observed that E. histolytica induced retraction, apoptosis and death of the human cells. LSEC retraction was detected earlier than cell death suggesting that reduced spreading of LSEC could account in vivo for the physical changes in tissue architecture allowing E. histolytica to pass the endothelial barrier and to penetrate into the liver parenchyma, a process possibly facilitated by the absence of tight junctions and by inflammation-induced gap formation between neighbouring cells [29]. In the presence of virulent amoebae, the LSEC network of actin stress fibers was disrupted, and the subcellular localisation of paxillin and phosphorylated focal adhesion kinase (FAK), key components of focal adhesion complexes formed upon activation of integrin receptors, was altered.…”