II. Modulating leukocyte recruitment to splanchnic organs to reduce inflammation

Abstract

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.

Isolation of Human Umbilical Vein Endothelial Cells and Their Use in the Study of Neutrophil Transmigration Under Flow Conditions

“…Examples include, but are not limited to, dermal microvascular endothelial cells 12 , liver sinusoidal endothelial cells 13 and endothelial cells from human umbilical vein 10 . Among them HUVEC gained wide popularity because of their relative ease of isolation and availability.…”

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

“…Although a number of different adhesion molecules (Pselectin and E-selectin, ␤2 integrins, ␣4, ICAM-1, VCAM-1) have been shown to play important roles in the pathophysiology of splanchnic organ injury subjected to IR, virtually none of these adhesion molecules have been demonstrated to be used by PMNs to bind to the sinusoidal endothelium (SECs) during liver IR. 40 Newer data demonstrates, for the first time, that PMNs use CD44 to bind to hyaluronan expressed by SECs to promote their adhesion and extravasation during inflammation. These studies may have important therapeutic ramifications because it is known that adherent PMNs become metabolically activated and transmigrate through SECs to the underlying hepatocytes where they generate additional reactive oxygen metabolites in conjunction with the release of extracellular matrix-degrading enzymes such as collagenase and matrix metalloproteinases.…”

Intravascular Immune Surveillance by CXCR6+ NKT Cells Patrolling Liver Sinusoids

“…The accumulation of lymphocytes in liver sinusoids (devoid of E/P-selectins, PECAM, CD34, and VE-cadherin, and low in VCAM-1) appears to result from mechanisms distinct from those involved in multistep extravasation of intravascular lymphocytes [14]. Accumulation of CD1d-reactive T cells in the liver has been shown to require LFA-1 expression on liver cells other than NKT cells [15], which implicates hematopoietic cells such as Kupffer cells in capture of NKT cells since endothelial cells do not express LFA-1.…”