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).