TY - JOUR
T1 - Mechanisms of gut barrier failure in the pathogenesis of necrotizing enterocolitis
T2 - Toll-like receptors throw the switch
AU - Hackam, David J.
AU - Good, Misty
AU - Sodhi, Chhinder P.
N1 - Funding Information:
Grant support: DJH is supported by R01GM078238 and RO1DK08752 from the National Institute of Health.
PY - 2013/5
Y1 - 2013/5
N2 - Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal causes in premature infants, and its overall survival has not improved in the past three decades. While the precise cause of NEC remains incompletely understood, we and others have shown that a major predisposing factor in the development and propagation of NEC is a breakdown of the intestinal barrier which leads to bacterial translocation and systemic sepsis. In seeking to identify the causes involved, we and others have also determined that activation of the receptor for bacterial endotoxin, namely toll-like receptor 4 (TLR4), is required for the development of intestinal barrier failure leading to NEC. We have also shown that the premature infant is endowed with strategies that can either limit or promote the extent of TLR4 signaling within the gut, which together determine the relative propensity with which NEC develops. In this review, we highlight the evidence for TLR4 signaling in the pathogenesis of NEC through a survey of its effects on gut barrier failure. We identify how TLR4 regulation within the gut can explain the unique susceptibility of the premature infant to the development of NEC, and highlight how strategies to limit the degree of TLR4 signaling can serve as novel therapeutic approaches for this devastating disease.
AB - Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal causes in premature infants, and its overall survival has not improved in the past three decades. While the precise cause of NEC remains incompletely understood, we and others have shown that a major predisposing factor in the development and propagation of NEC is a breakdown of the intestinal barrier which leads to bacterial translocation and systemic sepsis. In seeking to identify the causes involved, we and others have also determined that activation of the receptor for bacterial endotoxin, namely toll-like receptor 4 (TLR4), is required for the development of intestinal barrier failure leading to NEC. We have also shown that the premature infant is endowed with strategies that can either limit or promote the extent of TLR4 signaling within the gut, which together determine the relative propensity with which NEC develops. In this review, we highlight the evidence for TLR4 signaling in the pathogenesis of NEC through a survey of its effects on gut barrier failure. We identify how TLR4 regulation within the gut can explain the unique susceptibility of the premature infant to the development of NEC, and highlight how strategies to limit the degree of TLR4 signaling can serve as novel therapeutic approaches for this devastating disease.
KW - Bacterial translocation
KW - Necrotizing enterocolitis
KW - Neonatal intestinal barrier
KW - Toll-like receptor 4 regulation (TLR4)
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UR - http://www.scopus.com/inward/citedby.url?scp=84876721004&partnerID=8YFLogxK
U2 - 10.1053/j.sempedsurg.2013.01.003
DO - 10.1053/j.sempedsurg.2013.01.003
M3 - Article
C2 - 23611610
AN - SCOPUS:84876721004
SN - 1055-8586
VL - 22
SP - 76
EP - 82
JO - Seminars in pediatric surgery
JF - Seminars in pediatric surgery
IS - 2
ER -