Influence of Labor on Neonatal Neutrophil Apoptosis, and Inflammatory Activity

Weinberger, Barry; Vetrano, Anna M.; Syed, Kirin; Murthy, Sowmya Raveendra; Hanna, Nazeeh; Laskin, Jeffrey D.; Laskin, Debra L.

doi:10.1203/pdr.0b013e318045be38

Cited by 12 publications

(11 citation statements)

References 38 publications

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“…The present studies show that both adult and neonatal neutrophils constitutively generate significant quantities of H 2 O 2 . However, the rate of production and total amount of H 2 O 2 generated were greater in neonatal cells, which is consistent with our previous observations (18). MEHP was found to stimulate H 2 O 2 production by neonatal, but not adult neutrophils.…”

Section: Discussionsupporting

confidence: 93%

“…Subjects were excluded with clinical evidence of chorioamnionitis or other perinatal infections (maternal fever, uterine tenderness, or foul-smelling amniotic fluid). Subjects experiencing labor were excluded because labor is associated with an inflammatory phenotype in neonatal neutrophils (18). Neutrophils were isolated by dextran sedimentation, followed by Ficoll gradient centrifugation and hypotonic lysis of erythrocytes (19).…”

Section: Methodsmentioning

confidence: 99%

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Inflammatory Effects of Phthalates in Neonatal Neutrophils

et al. 2010

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IV infusion of crystalloid fluids and drugsBased on the results of the safety assessment, CDRH concludes that there is little to no risk posed by patient exposure to the amount of DEHP released from PVC IV bags following infusion of crystalloid fluids (e.g., normal saline, D5W, Ringers Lactate). Further, there is little risk posed by exposure to the amount of DEHP released from PVC bags used to store and administer drugs that require a pharmaceutical vehicle for solubilization, when label instructions are followed. Total Parenteral Nutrition (TPN)The dose of DEHP received by adult patients receiving TPN admixtures is estimated to be less than the TI, suggesting that there is little concern for DEHP-mediated effects in these patients. In addition, non-PVC bags and tubing are typically used to administer TPN, further lessening the concern about DEHP-mediated effects.The dose of DEHP received by neonates undergoing TPN supplementation is uncertain. The results of one study suggest that neonates can receive a very high dose of DEHP, whereas another suggests that neonates receive doses of DEHP from TPN that are equivalent to the TI. Therefore, depending on the data used to derive the TI/dose ratio, neonates receiving TPN admixtures with lipid may be at increased risk of DEHP-mediated adverse effects. Blood transfusionRelatively high doses of DEHP can be received by patients who are transfused with large volumes of blood and blood products over a short period (e.g., trauma or surgical patients receiving massive transfusions). However, the TI/dose ratio for this procedure is likely to overestimate the actual risk to these patients, since the TI is intended to be protective for longterm exposures, compared to relatively short-term exposure in acute transfusions. In contrast, a patient undergoing a routine, elective surgical procedure typically receives about two units of packed red blood cells. Transfusion of this volume of blood will result in a DEHP dose equivalent to the TI value, approximately 0.5 mg/kg/day. Long-term transfusion of blood to patients with anemia results in a DEHP dose about an order of magnitude lower. Similarly, infants who receive replacement transfusions in the NICU receive relatively small DEHP doses from the transfusions. Apheresis donors are exposed to relatively little DEHP when the dose is time-averaged over an extended period. Consequently, there is little concern about DEHP-associated adverse effects developing in persons donating platelets or plasma.Two subpopulations of patients that may be at increased risk from exposure to DEHP following transfusions are infants undergoing exchange transfusion and adults undergoing ECMO. However, neither of these procedures is done very often, so the patient population exposed to relatively large doses of DEHP via exchange transfusion or replacement transfusion of adults on ECMO is expected to be small. Cardiopulmonary bypass and ECMOThe aggregate dose of DEHP received by adults undergoing cardiopulmonary bypass procedures may equal or exceed the TI in...

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Inflammatory Effects of Phthalates in Neonatal Neutrophils

et al. 2010

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“…Nevertheless, the response to TLR1/2 stimulation by both preterm and term neonatal PMNs with increased IL-8 secretion regardless of the antenatal inflammatory state suggests a developmental tendency towards the proinflammatory state in newborn infants as compared to adults. Along those lines, we also detected no differences in IL-8 secretion following PAM3CSK4 stimulation of PMNs isolated from infants born by cesarean section versus vaginal delivery (data not shown) consistent with previous studies [29] , although a difference might have been expected given more recent reports [30,31] .…”

Section: Discussionsupporting

confidence: 92%

Toll-Like Receptor 1/2 Stimulation Induces Elevated Interleukin-8 Secretion in Polymorphonuclear Leukocytes Isolated from Preterm and Term Newborn Infants

Thornton

Yost

2011

Neonatology

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Background: Neonatal neutrophil dysfunction contributes to inflammatory tissue damage in newborn infants. Toll-like receptors (TLRs) activate the innate immune response through recognition of pathogen-associated molecular patterns. Expression and function of TLRs by neonatal neutrophils has not well been characterized. Objective: We hypothesized that, compared to polymorphonuclear leukocytes (PMNs) isolated from adults, neonatal PMNs isolated from either term or preterm infants express and release different levels of inflammatory cytokines and chemokines in response to stimulation with TLR1–9 agonists. Methods: We stimulated PMNs isolated from preterm (n = 12) and term (n = 10) infants as well as adults (n = 10) with agonists recognized by TLRs1–9 and quantified chemokine and cytokine expression and secretion by ELISA and Luminex® multiplex quantification assay. Results: Neonatal and adult PMNs stimulated with agonists recognized by TLRs1–9 differentially secrete inflammatory products. Signaling via TLR2 heterodimers is a potent mechanism for release of interleukin-8, a critical proinflammatory chemokine, by neonatal PMNs – a previously unrecognized facet of neonatal inflammation. Following TLR1/2 (PAM3CSK4) stimulation, interleukin-8 secretion by neonatal PMNs, whether term or preterm, substantially exceeds that of adult PMNs assayed in parallel. Conclusions: These studies provide new insights relevant to the inflammatory biology of neonates, both term and preterm, and implicate exaggerated PMN recruitment in neonatal syndromes of dysregulated inflammation such as necrotizing enterocolitis or neonatal chronic lung disease.

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“…NOX-1 is the major enzymatic mediator of superoxide anion generation in neutrophils [24]. Previous studies have shown that neonatal neutrophils produce robust quantities of superoxide anion and inflammatory eicosanoids after stimulation with inflammatory stimuli such as LPS [25]. Our findings suggest that bilirubin induces these oxidative and inflammatory responses in neonatal neutrophils at early time points.…”

Section: Discussionsupporting

confidence: 50%

Effects of Bilirubin on Neutrophil Responses in Newborn Infants

et al. 2012

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Background: Newborns are susceptible to inflammatory diseases due to defects in clearing activated immune cells from tissues. Therefore, mechanisms have likely evolved to protect neonates from leukocyte-mediated cytotoxicity. Bilirubin has antioxidant activity, and it is possible that it also exerts effects on cellular immune responses in jaundiced infants. Objectives: We hypothesize that bilirubin increases expression of antioxidant genes and decreases production of inflammatory proteins in neonatal neutrophils. Methods: Neutrophils were isolated from umbilical cord blood, and from adults for comparison, and treated with bilirubin (10–300 µmol/l, equivalent to unbound bilirubin 3–40 nmol/l), in the presence or absence of lipopolysaccharide (LPS). Expression of genes for antioxidant enzymes [superoxide dismutase (SOD), heme-oxygenase-1 (HO-1)] and heme-dependent enzymes involved in inflammation [NADPH oxidase-1 (NOX-1), cyclooxygenase-2 (COX-2)] was measured by PCR. Inflammatory cytokines were measured by bead array analysis using flow cytometry. Results: We found that LPS induced production of interleukin (IL)-8, IL-1β, and macrophage inhibitory protein-1β (MIP-1β). Bilirubin increased basal production of IL-8 and IL-1β, but downregulated LPS-induced generation of IL-8 and MIP-1β. It also upregulated SOD and HO-1 gene expression. We observed an unexpected bilirubin-induced increase in gene expression of NOX-1 in LPS-activated cells, and of COX-2 in both resting and activated cells. Conclusions: These findings suggest that bilirubin suppresses inflammation and increases antioxidant enzyme generation in activated neonatal neutrophils. The unexpected increases in NOX-1 and COX-2 expression may represent an early response, with physiologic effects mitigated by increased antioxidant activity. Further studies will be needed to define levels of bilirubin that optimize its protective effects, while minimizing potential inflammatory toxicity.

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Influence of Labor on Neonatal Neutrophil Apoptosis, and Inflammatory Activity

Cited by 12 publications

References 38 publications

Inflammatory Effects of Phthalates in Neonatal Neutrophils

Inflammatory Effects of Phthalates in Neonatal Neutrophils

Toll-Like Receptor 1/2 Stimulation Induces Elevated Interleukin-8 Secretion in Polymorphonuclear Leukocytes Isolated from Preterm and Term Newborn Infants

Effects of Bilirubin on Neutrophil Responses in Newborn Infants

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