Figure 3:
Schematic representation of the proposed mechanism involved in the
inflammatory response, resident macrophage activation, mechanisms
underlying the Inhibition of the contractile activity of the smooth
muscle of the intestine following abdominal surgery and potential
pharmacological targets. Intestinal manipulation and increased
intestinal permeability results in the passage of bacteria and
liposaccharides on the one hand and increased tissue degradation
products on the other. Binding to TLRs results in activation of
intracellular signals with increased transcription of pro-inflammatory
genes and release of cytokines (TNFα, IL1β, IL6) and chemokines (MCP1,
MIP1α), including upregulation of endothelial adhesion molecules such as
ICAM1. This leads to an influx of leukocytes into the muscularis
externa, followed by increased production of NO and PGs (via
upregulation of iNOS and COX2) by resident macrophages and leukocytes,
inhibiting contraction of intestinal smooth muscle. The secretion of ACh
by enteric neurons, stimulated by vagal efferences, leads to activation
of 7 αAChR receptors that inhibits TNF production.
Pharmacological targets:
- Inhibitor of p38MAK and NF-kB activation: Semapimod, CPSI 2634
- Inhibitor of MAP Kinase: Carbon Monoxide (CO)
- Inhibition of ICAM-1: ICAM antisense oligonucleotide ISIS 3082
- Stimulation of the release of acetylcholine from enteric neurons:
selective 5HT4 agonists (mosapride and prucalopride).
Abbreviations:
TJ, tight junction; TLR, toll-like receptor; LPs, liposaccharide; 7αAChR
α7-subtype of the nicotinic acetylcholine receptor; PAR2,
proteinase-activated receptor-2; ICAM-1, intercellular adhesion
molecule-1; LFA-1, lymphocyte function-associated antigen-1; MAP,
Mitogen-activated protein; JNK, c-Jun N-terminal kinase; NF-kB, nuclear
factor kB; STATS, signal transducers and activator of transcription; NO,
nitric oxide; PGs, prostaglandin; Cox-2, cyclooxygenase 2 ; iNOS,
inducible nitric oxide synthase; LFA-1, lymphocyte function-associated
antigen-1.