Recently, a drug discovery approach has revealed a novel class of TLR4 inhibitors which are being developed for personalized approaches to NEC treatment.
With experimental NEC, SIGIRR-/- mice had significantly more intestinal interleukin (IL)-1β, KC (mouse homolog to IL-8), intercellular adhesion molecule-1 (ICAM-1), and interferon-beta (IFN-β) expression in association with the amplified TLR pathway activation.
In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.
We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation.
Enterocyte proliferation was detected in IEC-6 cells or in ileum or colon from wild-type, TLR4-mutant, or TLR4(-/-) mice after induction of NEC or endotoxemia. beta-Catenin signaling was assessed by cell fractionation or immunoconfocal microscopy to detect its nuclear translocation.
IL-6-174 genotypes were not associated with CLD and/or NEC, but the CC genotype was correlated with septicemia in both univariate and multivariate analyses (P = .027).
In the NEC model group, Toll-like receptor (TLR)4, nuclear factor NF-κB (NF-κB), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 were upregulated.
Tissue levels of TNF-α, IL-6 and HMGB1 were significantly elevated in the NEC group, whereas those in the treatment group were decreased to similar values as in the control group.
XBP1 splicing, ER stress and the UPR in NEC are associated with increased IL6 and IL8 expression levels, altered T cell differentiation and severe epithelial injury.
These were achieved partly through restoration of VDR and suppression of TLR4.ConclusionNEC infants have lower levels of vitamin D. The vitamin D/VDR pathway protects against intestinal injury of NEC partly through suppressing the expression of TLR4.
Serum levels of endocan, IL-33, CRP, and IL-6 were significantly higher in the NEC group compared to the control group at the first, third, and seventh days (p < .05).
This article discusses the state of the science of the molecular mechanisms involved in TLR4-mediated inflammation during NEC and the development of new therapeutic strategies to prevent NEC.
Accordingly, using human and mouse fetal intestinal models, we have shown that B. fragilis with PSA and PSA alone inhibits IL-1β-induced IL-8 inflammation in fetal and NEC intestine.
Tissue levels of TNF-α, IL-6 and HMGB1 were significantly elevated in the NEC group, whereas those in the treatment group were decreased to similar values as in the control group.
To observe the effect of enteral supplement of insulin-like growth factor I (IGF-1) on dynamic changes of TLR4, NF-κB, IL-6, SIgA and MUC2 in intestinal tissues of neonatal rats, and to investigate the protective effects and possible mechanisms of IGF-1 on necrotizing enterocolitis (NEC).
Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52).
Our findings suggest that TNF-alpha induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC.