P107. Action of leukocytapheresis is associated with calcitonin gene-related peptide induction in colitis models
H. Yamasaki1, K. Mitsuyama1, H. Takedatsu1, T. Kobayashi1, K. Kuwaki1, K. Nagayama1, S. Yoshioka1, O. Tsuruta1, M. Sata1, 1Kurume University School of Medicine, Division of Gastroenterology, Department of Medicine, Kurume, Japan
Leukocytapheresis (LCAP) has been reported to be a safe and effective treatment for active ulcerative colitis (UC), but the mechanism underlying the effect is largely unknown. Using a rat dextran sulfate sodium-induced colitis model, we previously demonstrated that an increase in colonic blood flow observed during LCAP treatment is responsible for the induction of calcitonin gene-related peptide (CGRP), a vasodilative neuropeptide. Recently, CGRP has also been shown to be involved in potent tissue repair and anti-inflammatory actions. We addressed whether the action of LCAP depends on CGRP induction.
An HLA-B27 transgenic rat model of chronic colitis was treated with three weekly sessions of LCAP (LCAP column or a sham column). The effects of LCAP on clinical and endoscopic disease activity, bone marrow cell induction, and colonic blood flow were then examined. The tissue mRNA levels of CGRP and its receptors, RAMP1 and CRLR, were also determined using real time-PCR. Changes in these LCAP effects after the intravenous administration of a CGRP antagonist (CGRP8–37, 100 µg/kg) were also observed. In a second experiment, the effect of the intravenous administration of CGRP (400 µg/µL/day) or saline on disease activity, bone marrow cell induction, and colonic blood flow were investigated in a colitis rat model.
Treatment with the LCAP column, but not the sham column, significantly improved the clinical disease activity (P = 0.049) and the endoscopic disease activity (P = 0.034), induced the bone marrow cells (P = 0.032), and enhanced the colonic blood flow (P = 0.015) in association with an increase in the CGRP mRNA levels (P = 0.029). In contrast, the mRNA levels of the CGRP receptors, RAMP1 and CRLR, were not affected by LCAP. These LCAP actions were abolished by pretreatment with a CGRP antagonist, suggesting that LCAP activity depends on CGRP induction. Similar to the LCAP effect, the administration of CGRP, but not a control administration, improved the clinical disease activity (P = 0.009) and the endoscopic disease activity (P = 0.009), induced the bone marrow cells (P = 0.004), and enhanced the colonic blood flow (P = 0.032).
The tissue repair and anti-inflammatory actions of LCAP are associated with its induction of CGRP. CGRP is an attractive, novel therapeutic target for the treatment of UC patients.
- Posted in: Poster presentations: Basic Science (2013)