Mast cells
Several avenues of research and treatment have been and are being
considered, depending on the pathophysiology and timing of ileus, with
the initial focus on mast cells and their neuronal interactions (figure
2). The activation and degranulation of mast cells is a key point in the
inflammatory phenomena of ileus as described above. An NGF antagonist is
one of the first targets used to inhibit their activation. Indeed, mast
cells are activated by NGF via the high-affinity NGF receptor,
tropomyosin receptor kinase A (TrkA)(Marshall et al., 1990; Kawamoto et
al., 2002). Berdun et al. showed in a mouse model that treatment
with an NGF antagonist K252a prevented degranulation of mast cells and
decreased the expression of inflammatory markers such as IL6 (Berdún et
al., 2015b). Similarly, Jardi et al. suggested that
NGF-TrkA-dependent pathways are involved in the colonic contractile
alterations observed upon exposure to oral ovalbumin (OVA)-induced MCs
hyperactivity in rats. They observed spontaneous colonic activityin vivo and in vitro modified by OVA, an effect prevented
by K252a (Jardí et al., 2012). The same team studied the density of mast
cells and their proteases, tryptases and chymase at several stages of
the surgical procedure (Berdún et al., 2015a). There was a difference in
chymase and tryptase concentration between the cholecystectomy group and
the colectomy group suggesting a positive correlation between the
invasiveness of the surgical procedure and mast cell activation. There
was also a correlation between the peritoneal protease level and the
occurrence of POI after colectomy(Berdún et al., 2015a).
Aggregation by the IgE antigen bound to its high-affinity receptor on
mast cells triggers a complex series of biochemical events resulting in
the release of inflammatory mediators. The essential role of the
protein, tyrosine kinase Syk, in the degranulation of mast cells and
activation of resident macrophages has been described (Siraganian et
al., 2010). Van Bree et al. studied the Syk inhibitor, GSK
compound 143 (GSK143), in a mouse model of POI (figure2). Mice treated
with GSK 143 had significantly faster transit. In addition,in-vitro studies showed that GSK 143 blocked substance P and
decreased cytokine expression in lipopolysaccharide-treated macrophages
(van Bree et al., 2013).
The interaction of mast cells with afferent neurons via receptor
activity modifying protein 1 (RAMP1), calcitonin receptor-like (CALCRL)
and their roles in inflammation have been highlighted in studies
focusing on capsaicin and CGRP antagonists (figure 2) (Zittel et al.,
1994). In addition, a capsaicin-mediated effect on the acceleration of
gastric emptying has been described in mouse models (Plourde et al.,
1993). More recently, a new CGRP receptor antagonist (BIBN 4096BS) has
been studied in murine models, triggering a decrease in IL beta and IL6
mRNA expression in the muscularis externa 3 hours after surgery. In
addition, the authors refer to the presence of CGRP receptors in
resident macrophages (Glowka et al., 2015).
MCs stabilisation for the prevention of POI (figure 2) was assessed in a
pilot clinical trial involving 60 patients undergoing abdominal surgery
for gynaecological oncology and transit measurement by scintigraphy. Two
groups were compared: a Ketotifen-treated group and a placebo group.
Ketotifen is a second-generation H1-receptor antagonist/mast cell
stabiliser with potent anti-anaphylactic and anti-histamine properties.
It is almost completely absorbed after oral intake and has an
approximate bioavailability of 50%. Patients were dosed at 12 mg and 4
mg on the basis of adverse events occurring at 20 mg. Results showed
that Ketotifen significantly decreased gastric emptying time compared to
placebo (12 mg (gastric retention: median 3% (1-7), P=0.01), 4 mg
(gastric retention: 18% (3-45), P=0.6) compared to placebo (gastric
retention: 16% (5-75)). There was no significant difference in colonic
transit (The et al., 2009).