New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics.
Journal
Seminars in pediatric surgery
ISSN: 1532-9453
Titre abrégé: Semin Pediatr Surg
Pays: United States
ID NLM: 9216162
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
pmc-release:
01
06
2024
medline:
19
6
2023
pubmed:
9
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in premature infants that causes significant morbidity and mortality. Research efforts into the pathogenesis of NEC have discovered a pivotal role for the gram-negative bacterial receptor, Toll-like receptor 4 (TLR4), in its development. TLR4 is activated by dysbiotic microbes within the intestinal lumen, which leads to an exaggerated inflammatory response within the developing intestine, resulting in mucosal injury. More recently, studies have identified that the impaired intestinal motility that occurs early in NEC has a causative role in disease development, as strategies to enhance intestinal motility can reverse NEC in preclinical models. There has also been broad appreciation that NEC also contributes to significant neuroinflammation, which we have linked to the effects of gut-derived pro-inflammatory molecules and immune cells which activate microglia in the developing brain, resulting in white matter injury. These findings suggest that the management of the intestinal inflammation may secondarily be neuroprotective. Importantly, despite the significant burden of NEC on premature infants, these and other studies have provided a strong rationale for the development of small molecules with the capability of reducing NEC severity in pre-clinical models, thus guiding the development of specific anti-NEC therapies. This review summarizes the roles of TLR4 signaling in the premature gut in the pathogenesis of NEC, and provides insights into optimal clinical management strategies based upon findings from laboratory studies.
Identifiants
pubmed: 37290338
pii: S1055-8586(23)00056-2
doi: 10.1016/j.sempedsurg.2023.151309
pmc: PMC10330774
mid: NIHMS1906914
pii:
doi:
Substances chimiques
Toll-Like Receptor 4
0
Types de publication
Review
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
151309Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM141956
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007713
Pays : United States
Informations de copyright
Copyright © 2023. Published by Elsevier Inc.
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