Role of P‐selectin in radiation‐induced intestinal inflammatory damage

Abstract

SUMMARY The aims of our study were to characterize the dose-and time-dependent changes in endothelial P-selectin expression and the role of this adhesion molecule as a mediator of radiation-induced inflammation. For that purpose, endothelial P-selectin expression was measured by the radiolabeled antibody technique in control and irradiated mice at 2, 6, and 24 hr following abdominal irradiation with 4 or 10 Gy; leukocyte endothelial cell interactions were assessed using intravital microscopy in intestinal venules following irradiation at the aforementioned doses and times in C57BL/6 and P-selectindeficient mice. In wild-type mice, radiation induced a time-and dose-dependent upregulation of P-selectin and a significant increase in the flux of rolling leukocytes 2 hr after irradiation. Irradiation induced a significant increase in leukocyte adhesion that was dosedependent. Following irradiation, P-selectin-deficient mice did not show any increase in leukocyte rolling but did demonstrate a response in leukocyte adhesion similar to that of the wild-type mice. Radiation-induced dose-dependent histological inflammatory damage that did not differ between P-selectin-deficient and wild-type mice. We conclude that P-selectin is up-regulated following irradiation and is a key molecular determinant of leukocyte rolling but not leukocyte adhesion in this inflammatory condition. Therefore, isolated neutralization of this adhesion molecule is not an effective means for preventing radiation-induced inflammation.

Radiation-induced intestinal inflammation

“…Hallahan et al [16] showed in vitro that the lowest dose that induced translocation of P-selectin to the cell membrane was 2 Gy. Confirmatory evidence has been provided showing that P-selectin expression is significantly up-regulated in response to abdominal irradiation, and this regulation is dose-and time-dependent [6] . However, lack of P-selectin does not afford protection against radiationinduced inflammatory intestinal alterations probably because leukocyte adhesion is not solely a consequence of an increase in P-selectin mediated rolling; there is a release of proinflammatory mediators like PAF [5] or LTB4 [17] that may directly affect firm leukocyte adhesion.…”

“…Hallahan et al [19] showed that thoracic irradiation increases E-selectin expression in the pulmonary vascular endothelium of mice. In contrast, another study did not detect expression of this molecule in wild-type or in P-selectin deficient mice after abdominal irradiation at different doses (4, 10 Gy) and time (2 h or 24 h) points [6] . Recent studies have suggested that E-selectin could be involved in the antiinflammatory response after radiotherapy, mediating the drop in leukocyte adhesion after low dose irradiation (0.3-0.6 Gy) in vitro [20] .…”

“…This early inflammatory response has been implicated in the vascular alterations that result from radiation damage [6] . The development of an inflammator y response is a finely regulated process that involves sequential leukocyte-endothelial cell interactions composed of rolling, activation, adhesion and emigration phases.…”

Transfection of antisense core 2 β1,6-N-acetylglucosaminyltransferase-1 cDNA suppresses selectin ligand expression and tissue infiltration of B-cell precursor leukemia cells

“…19,20 The cells were stained with APC-Cy7-conjugated anti-human CD45 antibody (Becton Dickinson) and human-CD45 þ cells were counted by flow cytometry analysis.…”

Ferulic Acid Attenuates Adhesion Molecule Expression in Gamma-Radiated Human Umbilical Vascular Endothelial Cells

“…4) The survival rate increased in gene knockout mice lacking ICAM-1 or VCAM-1. 5) Remarkable progress has been made in recent years in designing new drugs targeting radiation-up-regulated adhesion molecules.…”