Abstract:Neonatal septic shock is a devastating condition associated with high morbidity and mortality. Definitions for the sepsis continuum and treatment algorithms specific for premature neonates are needed to improve studies of septic shock and assess benefit from clinical interventions. Unique features of the immature immune system and pathophysiologic responses to sepsis, particularly those of extremely preterm infants, necessitate that clinical trials consider them as a separate group. Keen clinical suspicion and… Show more
“…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.…”
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
“…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.…”
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
“…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).…”
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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