Intracellular signalling
Resident macrophages can also be stabilised by interfering with
intracellular signalling (figure 3) (Wehner et al., 2009). Semapimod
(CNI-1493, N, N-bis [3, 5diacethylphenyl] decanediamide tetrakis
[amidinohydrazone]) is an inhibitor of p38MAK and NF-kB activation
and COX2 induction by TLR ligands (Bianchi et al., 1995). Studies
carried out by Wang et al. show that Semapimod desensitises TLR
signalling via its effect on the TLR chaperone gp96(Wang et al., 2016).
Work on the mouse model of POI has provided encouraging results via
several routes of administration. Injection of semapimod (CNI-1493) into
the cerebral ventricles is one route for pharmacological stimulation of
the vagus nerve and for reproducing its anti-inflammatory and motor
action on the digestive tract (The et al., 2011). Furthermore,
intravenous (CNI-1403) and oral (CPSI-2364) administration of semapimod
reproduces anti-inflammatory action in a murine model and reduces the
suppressant effect of muscle contraction during POI (Wehner et al.,
2012). MAPKs can be modulated by administering inhaled carbon monoxide
(CO) or locally by intraperitoneal administration with promising results
in mouse models of POI(De Backer et al., 2009; Van Dingenen et al.,
2018). The mechanisms of CO action have been described and reviewed in
depth by Babu et al . The mechanisms of action of CO on POI at
MAPK level include suppression of ERK MAPK (extracellular
signal-regulated kinases – mitogen activated kinase) phosphorylation
via a soluble guanine cyclase (sGC)-dependent pathway and induction of
haem oxygenase 1 (HO1) via phosphorylation of p38 MAPK (Babu et al.,
2015). More recently, the direct induction of HO1 and its
anti-inflammatory and POI-preventing action have been reported in mice
following the intraperitoneal administration of Hemin (Van Dingenen et
al., 2020).
The afore-mentioned studies using CO inhalation also revealed the
significant temporal induction of IL10 in the external musculature
during the inflammatory response after surgical manipulation of the
intestine. In addition, CO significantly increased postoperative IL10
expression and work on an ileus model with IL10 KO mice highlighted a
role for IL10 in the resolution of the inflammatory phase (Stoffels et
al., 2009). However, these results have been challenged by recent
studies which demonstrated a pro-inflammatory effect of IL10 (Stein et
al., 2018). Finally, extravasation and diapedesis of leukocytes also
play an important role in local inflammation. The et al showed that
inhibition of adhesion molecules such as ICAM-1 with an antibody (ICAM
antisense oligonucleotide ISIS 3082) reduces inflammation induced by
intestinal manipulation in a murine model (The et al., 2005).