The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis

Caplan, Michael S.; Simon, Dyan; Jilling, Tamás

doi:10.1053/j.sempedsurg.2005.05.002

Cited by 128 publications

(111 citation statements)

References 34 publications

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“…Neonatal TLR4 (receptor that recognizes LPS) deficient mice do not develop NEC (19). However, TLR4 signaling does not explain the induction of NEC by gram-positive bacteria (13), yeasts, or viruses (20)(21)(22), which do not provide the ligand for TLR4.…”

Section: Discussionmentioning

confidence: 99%

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

Ginzel

Klemann

et al. 2015

Pediatr Res

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Background: Necrotizing enterocolitis (NEC) is a lifethreatening gastrointestinal disease in premature infants with high mortality and morbidity with uncertain pathogenesis. Recent research focused on the role of intraluminal bacteria and lipopolysaccharide (LPS). However, an additional role of viral agents in the pathogenesis of NEC has recently been postulated. We assessed the role of polyinosinic:polycytidylic acid (pIC) mimicking viral dsRNA in contributing to the development of NEC in neonatal mice. Methods: Four-d-old C57BL/6J pups were stressed by asphyxia and hypothermia twice daily. Animals were either fed by formula only (FO), formula containing LPS or pIC. After 72 h, mice were euthanized, intestines harvested, and the severity of NEC was assessed. results: Breastfed mice showed no evidence of NEC. Very mild NEC-like lesions were observed in mice fed by FO. Supplementation of LPS or pIC to the formula led to increased intestinal tissue damage and inflammation compared with FO in a similar manner. conclusion: Our study demonstrates the ability of viral factors to induce NEC in neonatal mice even in the absence of LPS. Furthermore, we present a new mouse model of pIC-induced NEC which may be used to obtain further mechanistic insights in the pathogenesis of this disease.

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Section: Discussionmentioning

confidence: 99%

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

Ginzel

Klemann

et al. 2015

Pediatr Res

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“…Activation of the PAF receptor by PAF is associated with apoptosis through activation of caspases, loss of tight junctions, and increased activation of the TLR4 promoter. TLR4 is necessary for modulation of the processes that eliminate pathogenic microorganisms, but in infants with NEC, this pathway is aberrantly activated, leading to exaggerated production of proinflammatory mediators (17).…”

Section: Session Ii: Mechanisms Of Diseasementioning

confidence: 99%

New Therapies and Preventive Approaches for Necrotizing Enterocolitis: Report of a Research Planning Workshop

et al. 2007

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“…It has recently been reported that PAF-binding to its receptor induces the activation of Rho GTPase Rac1 by its guanine nucleotide exchange factor Tiam1, and a relocation of proteins Zonula Occludens-1 (ZO-1) and VE-cadherin from the inter-endothelial junctions, resulting in the formation of numerous gaps [7]. PAF has prolonged effects in vivo despite a very short plasma half-life suggesting the involvement of secondary mediators or, that a pool of PAF residing in the plasma membrane of the cells is released slowly over time [3]. PAF acts through specific receptors present on the membrane of responsive cells, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Elevated levels of PAF further induce expression of other inflammatory factors including TNF-α and IL-1β [2,3]. The production of PAF and the ensuing inflammatory response after injuries, such as trauma, haemorrhagic shock, sepsis, acute pancreatitis, and severe burns can lead to general organ dysfunction and failure, which has a mortality rate of >50% [4].…”

Section: Introductionmentioning

confidence: 99%

“…The production of PAF and the ensuing inflammatory response after injuries, such as trauma, haemorrhagic shock, sepsis, acute pancreatitis, and severe burns can lead to general organ dysfunction and failure, which has a mortality rate of >50% [4]. Inflammatory mediators, such as PAF, also play a key role in the pathogenesis of acute respiratory distress syndrome [4], and in necrotizing enterocolitis (NEC) [3,5]. In the latter case PAF, toll-like receptors and activation of the cytokine inflammatory cascade in concert play a pivotal role in the loss of an intact mucosal barrier, as well as in mucosal injury [6].…”

Section: Introductionmentioning

confidence: 99%

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GM2 activator protein inhibits platelet activating factor signaling in rats

Rigat¹,

Yeger²,

Shehnaz³

et al. 2009

Biochemical and Biophysical Research Communications

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Platelet activating factor (PAF), an endogenous bioactive phospholipid, has been documented as a pivotal mediator in the inflammatory cascade underlying the pathogenesis of many diseases including necrotizing enterocolitis. Much effort has been directed towards finding an effective in vivo inhibitor of PAF signaling. Here, we report that a small, highly stable, lysosomal lipid transport protein, the GM2 activator protein (GM2AP) is able to inhibit the inflammatory processes otherwise initiated by PAF in a rat model of necrotizing enterocolitis. Based on behavioral observations, gross anatomical observations at necropsy, histopathology and immunocytochemistry, the administration of recombinant GM2AP inhibits the devastating gastrointestinal necrosis resulting from the injection of rats with LPS and PAF. Recombinant GM2AP treatment not only markedly decrease tissue destruction, but also helped to maintain tight junction integrity at the gastrointestinal level as judged by contiguous Zonula Occludens-1 staining of the epithelial layer lining the crypts.

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The role of PAF, TLR, and the inflammatory response in neonatal necrotizing enterocolitis

Cited by 128 publications

References 34 publications

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

New Therapies and Preventive Approaches for Necrotizing Enterocolitis: Report of a Research Planning Workshop

GM2 activator protein inhibits platelet activating factor signaling in rats

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