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A key pathological feature of the systemic inflammatory response of sepsis/endotoxemia is the accumulation of neutrophils within the microvasculature of organs such as the liver, where they cause tissue damage and vascular dysfunction. There is emerging evidence that the vascular endothelium is critical to the orchestration of inflammatory responses to blood-borne microbes and microbial products in sepsis/endotoxemia. In this study, we aimed to understand the role of endothelium, and specifically endothelial TLR4 activation, in the regulation of neutrophil recruitment to the liver during endotoxemia. Intravital microscopy of bone marrow chimeric mice revealed that TLR4 expression by non-bone marrow-derived cells was required for neutrophil recruitment to the liver during endotoxemia. Furthermore, LPS-induced neutrophil adhesion in liver sinusoids was equivalent between wild-type mice and transgenic mice that express TLR4 only on endothelium (tlr4-/-Tie2tlr4), revealing that activation of endothelial TLR4 alone was sufficient to initiate neutrophil adhesion. Neutrophil arrest within sinusoids of endotoxemic mice requires adhesive interactions between neutrophil CD44 and endothelial hyaluronan. Intravital immunofluorescence imaging demonstrated that stimulation of endothelial TLR4 alone was sufficient to induce the deposition of serum-derived hyaluronan-associated protein (SHAP) within sinusoids, which was required for CD44/hyaluronan-dependent neutrophil adhesion. In addition to endothelial TLR4 activation, Kupffer cells contribute to neutrophil recruitment via a distinct CD44/HA/SHAP-independent mechanism. This study sheds new light on the control of innate immune activation within the liver vasculature during endotoxemia, revealing a key role for endothelial cells as sentinels in the detection of intravascular infections and coordination of neutrophil recruitment to the liver. [ABSTRACT FROM AUTHOR]

The article discusses a study on role of hydrogen sulfide in sepsis-associated liver injury. Topics include hepatic parenchyma which occurs due to intertwined mechanism, microcirculatory dysfunction of rat ischemia reperfusion model, and acetaminophen-induced hepatic intoxication. The study revealed that propargylglycine (PAG) is hepatoprotective in endotoxemia and inhibits the infiltration of detrimental neutrophil and improves perfusion.

After an ischemic episode, reperfusion causes profound oxidative stress in the vasculature of the afflicted tissue/ organ. The dysregulated accumulation of reactive oxygen species (ROS), such as superoxide, has been closely linked to the production and release of proinflammatory mediators, a profound increase in adhesion molecule expression by the vascular endothelium, and infiltration of neutrophils during ischemia-reperfusion (I/R). Superoxide dismutase (SOD) has been shown to protect tissues and organs against I/R-induced injury; however, the drag had to be continuously perfused or kidneys had to be occluded to prevent clearance. We used intravital microscopy, a system that allowed us to visualize neutrophil-endothelial interactions within the mesenteric postcapillary venules of cats subjected to I/R and tested the hypothesis that I/R-induced neutrophil recruitment was inhibited by treatment with SOD2/3. SOD2/3 is a chimeric fusion gene product that contains the mature SOD2 as well as the COOH-terminal "tail" of SOD3 and, unlike the three naturally occurring SODs (SOD1, SOD2, and SOD3), which bear a net negative charge at pH 7.4, SOD2/3 is positively charged and physiologically stable. Our results suggest that not only does SOD2/3 have a much greater efficacy in vivo than the native human SOD2, but its administration prevents I/R-induced neutrophil-endothelial cell interactions and microvascular dysfunction. Moreover, our data support the hypothesis that reactive oxidants mediate I/R-induced injury and that the chimeric recombinant SOD2/3 has the potential to be a therapeutic agent against this debilitating illness. [ABSTRACT FROM AUTHOR]

A hallmark feature of intestinal inflammation is the recruitment and extravasation of numerous cell types from the blood to the afflicted site. Much of what we know about the mechanisms of leukocyte recruitment to splanchnic organs comes from an extensive series of studies on neutrophils in the mesenteric microvasculature. In this themes article, we highlight the important findings from these experiments but also emphasize some of the limitations. In fact, there is a growing body of evidence that neutrophil recruitment may be quite different in the mesentery than in other splanchnic organs. For example, the molecular mechanisms underlying neutrophil recruitment into the liver are quite different than the mesentery and are dependent on the type of inflammatory disease. We also discuss the effect of modulating leukocyte recruitment to splanchnic organs in chronic inflammation and emphasize that the approaches that have been successful in acute inflammation may be less effective in such conditions as inflammatory bowel disease (IBD). One obvious reason for this observation is the growing body of evidence to suggest that the initiation and maintenance of IBD is, in part, due to dysregulated or inappropriately activated populations of infiltrating T lymphocyte subsets. Therefore, we also discuss some interesting new approaches to limiting lymphocyte recruitment into the inflamed intestine either by targeting T helper (Th)1 vs. Th2 lymphocytes or perhaps by allowing the recruitment of regulatory T cells. Inhibiting specific adhesion molecules or specific chemokine receptors may work in this regard. [ABSTRACT FROM AUTHOR]

Discusses a study which clarified the role of intercellular adhesion molecule-1 (ICAM-1)-mediated cell recruitment in chronic hepatic rejection. Discussion on liver transplantation; Illustration of a liver biochemistry analysis; Description of an immunohistochemistry stain for ICAM-1 antisense oligonucleotide.

Discusses a study which explored the molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation. Role of infiltrating neutrophils in ischemia reperfusion injuries; Details of the experimental protocol; Effects of anti-selectin therapy.

Investigates whether inducible nitric oxide (NO) synthase (iNOS) can modulate tumor necrosis factor-alpha (TNF-alpha)-induced leukocyte rolling. Effect of NO on cell adhesion molecules expression; Regulation of leukocyte rolling in the inflammatory response of NO derived from iNOS; Detection of low quantities of iNOS messenger ribonucleic acid.

Provides direct evidence supporting the concept that mast cells are critical for the pathogenesis of ischemia-reperfusion (I/R) injury in the small intestine. Two types of mast cells; Commonalities in the molecular mechanisms that underlie reperfusion injury in the intestine versus other tissues; Insensitivity of the connective tissue mast cells in skeletal muscle to I/R.