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).