Trinitrobenzene sulfonic acid-induced intestinal injury in neonatal mice activates transcriptional networks similar to those seen in human necrotizing enterocolitis

MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Cheng, Feng; Jiang, Rays H. Y.; Flores-Torres, Jaime; Torres, Benjamin A.; Maheshwari, Akhil

doi:10.1038/pr.2016.189

Cited by 35 publications

(31 citation statements)

References 37 publications

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“…This is supported by the finding that premature infants who developed NEC display a gut microbial dysbiosis with lower diversity and higher amounts of Gram‐negative bacteria prior to disease onset . Furthermore, the bacterial cell wall component LPS was found to be a top transcriptional upstream regulator in NEC . Interestingly, eradication of Gram‐negative bacteria with orally given aminoglycosides appears to be protective against NEC in premature infants .…”

Section: Discussionmentioning

confidence: 85%

Human lactoferrin attenuates the proinflammatory response of neonatal monocyte-derived macrophages

Wisgrill¹,

Wessely²,

Spittler

et al. 2018

Clinical and Experimental Immunology

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SummaryBioactive components of human milk, such as human lactoferrin (hLF), play an essential role in gut microbiome homeostasis and protection against neonatal inflammatory diseases. Neonatal intestinal macrophages display a proinflammatory profile that might contribute to inflammatory mucosal injury. Therefore, the aim of the study was to investigate the immunomodulatory effects of hLF on differentiation and activation of monocyte‐derived macrophages (moMϕ). Monocytes isolated from umbilical cord blood of term neonates and peripheral blood of healthy adults were differentiated in the absence or presence of hLF, and differentiation, apoptosis and phagocytosis were evaluated. Cytokine production, Toll‐like receptor (TLR) signalling and activation marker expression were investigated upon activation with lipopolysaccharide (LPS) and lipoteichoic acid (LTA) challenge. We demonstrate that hLF‐differentiated moMϕ exhibit decreased TLR‐4 expression, TLR signalling, proinflammatory cytokine secretion and intracellular tumour necrosis factor (TNF)‐α production. Investigation of differentiation markers, morphology and induction of apoptosis showed no alteration in lactoferrin‐differentiated moMϕ. Taken together, hLF promote anergic/anti‐inflammatory effects by TLR expression and pathway interference, resulting in a diminished proinflammatory moMϕ phenotype. The anergic/anti‐inflammatory properties of hLF might contribute to the prevention of harmful TLR‐mediated inflammatory disorders in the developing gut of premature infants.

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Section: Discussionmentioning

confidence: 85%

Human lactoferrin attenuates the proinflammatory response of neonatal monocyte-derived macrophages

Wisgrill¹,

Wessely²,

Spittler

et al. 2018

Clinical and Experimental Immunology

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ With uncertainties surrounding the reproducibility and efficacy of the HHF model, as well as concerns regarding the lack of translation to human patients, several new models have been developed that attempted to utilize inflammatory pathways rather than hypoxia to initiate NEC injuries. One example is the administration of trinitrobenzenesulfonic acid to ten day old mice, which acts as a hapten, binding to host proteins and generating an immune response that results in a mucosal injury, similar to that seen in NEC patients 33 . A second model, which has also produced intestinal damage analogous to human NEC patients, utilizes a disruption of Paneth cells, followed by enteral gavage feeding of bacteria of 14 day old mice 34 .…”

Section: Discussionmentioning

confidence: 99%

Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

Klinke

Vincent

Trochimiuk

et al. 2020

Sci Rep

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Various research models to induce necrotizing enterocolitis (NEC) in animals exist, yet significant differences in NEC severity between murine animal models and human patients persist. One possible explanation for the difference in severity may be the variance in neutrophil concentration among newborn humans (50-70%) in comparison to neonatal mice (10-25%). However, neutrophil activity has yet to be evaluated in NEC pathogenesis. Thus, the aim of the study was to evaluate the effects of altered neutrophil concentrations in neonatal mice while simultaneously undergoing a NEC induction. A total of 44 neonatal mice were included in this study and 40 were subjected to an established NEC induction paradigm and 4 were assigned a sham group. Of the 40 mice, 30 received granulocytecolony stimulating factor (G-CSF) on a daily basis, while 10 were used as controls (receiving inactivated G-CSF). Mice undergoing G-CSF treatment were further divided into two subgroups: (1) wildtype and (2) ELANE-knockout (KO). ELANE-KO mice are incapable of producing neutrophil elastase (NE) and were used to evaluate the role of neutrophils in NEC. For each of the groups, the following metrics were evaluated: survival, NEC severity, tissue damage, neutrophil count and activation, and NETs formation. An improved murine model of NEC was developed using (1) Lipopolysaccharides and Neocate gavage feeding, (2) hypoxia, and (3) G-CSF administration. The results suggest that the addition of G-CSF resulted in significantly elevated NEC manifestation rates with consequent tissue damage and intestinal inflammation, without affecting overall mortality. Animals without functioning NE (ELANE-KO) appeared to have been protected from NEC development. This study supports the importance of neutrophils in NEC pathogenesis. The optimized NEC induction paradigm, using G-CSF administration, resulted in elevated neutrophil counts, resembling those of neonatal humans. Elevation of neutrophil levels significantly improved NEC disease manifestation by modeling human physiology more accurately than current NEC models. Thus, in the future, murine NEC experiments should include the elevation of neutrophil levels to improve the transition of research findings from mice to humans.

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“…100 In this study, we sought transcriptional networks likely to be activated in human NEC and in a murine NEC model, where we used 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) to induce inflammatory intestinal injury in 10-day-old murine pups. 101 Interestingly, bacterial lipopolysaccharide (LPS) was predicted to be the top upstream transcriptional regulator in both human NEC and TNBS-mediated murine intestinal injury.…”

Section: What Is the Role Of Cytokines In The Pathogenesis Of Nec?mentioning

confidence: 99%

Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis

MohanKumar¹,

Namachivayam²,

Ho³

et al. 2017

Seminars in Perinatology

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Cytokines and growth factors play diverse roles in the uninflamed fetal/neonatal intestinal mucosa and in the development of inflammatory bowel injury during necrotizing enterocolitis (NEC). During gestational development and the early neonatal period, the fetal/premature intestine is exposed to high levels of many “inflammatory” cytokines and growth factors, first via swallowed amniotic fluid in utero and then, after birth, in colostrum and mother’s milk. This article reviews the dual, seemingly counter-intuitive roles of cytokines, where these agents play a “trophic” role and promote maturation of the uninflamed mucosa, but can also cause inflammation and promote intestinal injury during NEC.

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Trinitrobenzene sulfonic acid-induced intestinal injury in neonatal mice activates transcriptional networks similar to those seen in human necrotizing enterocolitis

Cited by 35 publications

References 37 publications

Human lactoferrin attenuates the proinflammatory response of neonatal monocyte-derived macrophages

Human lactoferrin attenuates the proinflammatory response of neonatal monocyte-derived macrophages

Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

Cytokines and growth factors in the developing intestine and during necrotizing enterocolitis

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