Pathophysiology and Treatment of Septic Shock in Neonates

Wynn, James L.; Wong, Hector R.

doi:10.1016/j.clp.2010.04.002

Cited by 208 publications

(197 citation statements)

References 313 publications

(298 reference statements)

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“…Low expression of MHC-II on the surface of cord blood monocytes, lower levels of IL-12p40 in cord blood, and decreased ex vivo production of TNF by whole blood exposed to LPS were observed in newborns who subsequently developed sepsis (66,67). However, following infection, newborn infants can develop a widespread state of innate immune overactivation leading to septic shock, organ damage, and death (68). Interestingly, MIF inhibition in infected newborn mice reduces systemic inflammatory response, bacterial proliferation, and mortality.…”

Section: Discussionmentioning

confidence: 99%

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

Roger

Schneider

Weier

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The vulnerability to infection of newborns is associated with a limited ability to mount efficient immune responses. High concentrations of adenosine and prostaglandins in the fetal and neonatal circulation hamper the antimicrobial responses of newborn immune cells. However, the existence of mechanisms counterbalancing neonatal immunosuppression has not been investigated. Remarkably, circulating levels of macrophage migration inhibitory factor (MIF), a proinflammatory immunoregulatory cytokine expressed constitutively, were 10-fold higher in newborns than in children and adults. Newborn monocytes expressed high levels of MIF and released MIF upon stimulation with Escherichia coli and group B Streptococcus, the leading pathogens of early-onset neonatal sepsis. Inhibition of MIF activity or MIF expression reduced microbial product-induced phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases and secretion of cytokines. Recombinant MIF used at newborn, but not adult, concentrations counterregulated adenosine and prostaglandin E2-mediated inhibition of ERK1/2 activation and TNF production in newborn monocytes exposed to E. coli. In agreement with the concept that once infection is established high levels of MIF are detrimental to the host, treatment with a small molecule inhibitor of MIF reduced systemic inflammatory response, bacterial proliferation, and mortality of septic newborn mice. Altogether, these data provide a mechanistic explanation for how newborns may cope with an immunosuppressive environment to maintain a certain threshold of innate defenses. However, the same defense mechanisms may be at the expense of the host in conditions of severe infection, suggesting that MIF could represent a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis.newborns | Escherischia coli | prostaglandin | adenosine | sepsis

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Section: Discussionmentioning

confidence: 99%

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

Roger

Schneider

Weier

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The innate immune system plays a critical role in a successful host response to sepsis, particularly in the neonate (18). Multiple developmental alterations of innate host response capabilities are present in neonates compared with older age groups, including pathogen recognition receptors, inflammatory signaling pathways and overall innate immune cellular function (19)(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Wynn

Cvijanovich²,

Allen

et al. 2011

Mol Med

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126

109

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Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2-5 years, n = 54) and schoolage (≥6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.

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“…Most babies with HDN are "well looking" in contrast to bleeding due to other causes (Sepsis, DIC and NEC) in which the baby appears sick 8 . 10 .…”

Section: Introductionmentioning

confidence: 99%

Hemorrhagic Disease of Newborn: A Prospective Study of Clinical Features and Outcome.

Gopchade¹

2018

ijmsci

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Pathophysiology and Treatment of Septic Shock in Neonates

Cited by 208 publications

References 313 publications

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Hemorrhagic Disease of Newborn: A Prospective Study of Clinical Features and Outcome.

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