Neonatal Inflammation Research Articles

One bout of neonatal inflammation impairs adult respiratory motor plasticity in male and female rats.

Neonatal inflammation is common and has lasting consequences for adult health. We investigated the lasting effects of a single bout of neonatal inflammation on adult respiratory control in the form of respiratory motor plasticity induced by acute intermittent hypoxia, which likely compensates and stabilizes breathing during injury or disease and has significant therapeutic potential. Lipopolysaccharide-induced inflammation at postnatal day four induced lasting impairments in two distinct pathways to adult respiratory plasticity in male and female rats. Despite a lack of adult pro-inflammatory gene expression or alterations in glial morphology, one mechanistic pathway to plasticity was restored by acute, adult anti-inflammatory treatment, suggesting ongoing inflammatory signaling after neonatal inflammation. An alternative pathway to plasticity was not restored by anti-inflammatory treatment, but was evoked by exogenous adenosine receptor agonism, suggesting upstream impairment, likely astrocytic-dependent. Thus, the respiratory control network is vulnerable to early-life inflammation, limiting respiratory compensation to adult disease or injury.

Umbilical Cord Serum Ferritin Concentration is Inversely Associated with Umbilical Cord Hemoglobin in Neonates Born to Adolescents Carrying Singletons and Women Carrying Multiples

It has been proposed that the fetus prioritizes iron for hemoglobin production over delivery to tissues. However, few studies have evaluated the interrelations between hemoglobin and multiple iron status biomarkers in umbilical cord blood. A full understanding is needed of how these parameters influence each other within cord blood to fully interpret iron and hematologic status at birth. We evaluated the determinants of neonatal hemoglobin and assessed the interrelations between hemoglobin, serum iron status indicators, and serum iron regulatory hormones in healthy neonates. This was an observational study that assessed umbilical cord hemoglobin (Hb), serum ferritin (SF), erythropoietin (EPO), soluble transferrin receptor (sTfR), serum iron, hepcidin, vitamin B-12, folate, IL-6, and CRP measured in 234 neonates born to adolescents or to women carrying multiples. Correlations between these indicators were evaluated and mediation models consistent with the observed significant determinants of cord Hb concentrations were developed. A highly significant inverse association was found between cord SF and Hb concentrations that was not attributable to neonatal or maternal inflammation (as measured by IL-6 and CRP). The inverse association was present in the combined cohort, as well as in the adolescent and multiples cohorts independently. Mediation analyses found that EPO and hepcidin had significant indirect effects on cord Hb, associations that are explicable by mediation through SF and sTfR. In contrast to observations made in older infants, a highly significant inverse association between Hb and SF, as well positive associations between Hb and both sTfR and EPO, were observed in umbilical cord blood from neonates born to adolescents or women carrying multiples. These findings, combined with review of the published literature, indicate a need for analysis of the relations between multiple parameters to assess iron and hematologic status at birth. These clinical trials were registered at clinicaltrials.gov as NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802) and NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902).

White matter microstructure and cognitive outcomes in relation to neonatal inflammation in 6-year-old children born preterm.

BackgroundCognitive outcomes in preterm (PT) children have been associated with microstructural properties of white matter. PT children who experienced neonatal inflammatory conditions have poorer cognitive outcomes than those who did not. The goal of this study was to contrast white matter microstructure and cognitive outcomes after preterm birth in relation to the presence or absence of severe inflammatory conditions in the neonatal period.MethodsPT children (n = 35), born at gestational age 22–32 weeks, were classified as either PT+ (n = 12) based on a neonatal history of inflammatory conditions, including bronchopulmonary dysplasia, necrotizing enterocolitis or culture positive sepsis, or PT- (n = 23) based on the absence of the three inflammatory conditions. Full term (FT) children (n = 43) served as controls. Participants underwent diffusion MRI and cognitive testing (intelligence, reading, and executive function) at age 6 years. The corpus callosum was segmented into 7 regions using deterministic tractography and based on the cortical projection zones of the callosal fibers. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for each segment. General linear models with planned contrasts assessed group differences in FA, MD and cognitive outcomes. Pearson correlations assessed associations of white matter metrics and cognitive outcome measures.ResultsFA was significantly lower and MD was significantly higher in PT+ compared to PT- or FT groups in multiple callosal segments, even after adjusting for gestational age. Executive function scores, but not intelligence or reading scores, were less favorable in PT+ than in PT- groups. Among the entire sample, occipital FA was significantly correlated with IQ (r = 0.25, p < 0.05), reading (r = 0.32, p < 0.01), and executive function (r = −0.28, p < 0.05) measures. Anterior frontal FA and superior parietal FA were significantly correlated with executive function (r = −0.25, r = 0.23, respectively, p < 0.05).ConclusionsWe observed differences in the white matter microstructure of the corpus callosum and in the cognitive skills of 6-year-old PT children based on their history of neonatal inflammation. Neonatal inflammation is one medical factor that may contribute to variation in long-term neurobiological and neuropsychological outcomes in PT samples.

Neonatal Lipopolysaccharide Challenge Induces Long-lasting Spatial Cognitive Impairment and Dysregulation of Hippocampal Histone Acetylation in Mice

Neonatal inflammation induces long-term effects on brain function. We investigated the effects of systematic neonatal inflammation using lipopolysaccharide (LPS) injection at postnatal day 3 (P3) and P5 in a mouse model of spatial memory capacity measured using a Morris water maze (MWM) task in adulthood. Subsequently, we assessed histone acetylation and immediate-early response gene expression (c-Fos and brain-derived neurotrophic factor) in the hippocampus in response to MWM acquisition training. The LPS-treated mice exhibited a significant spatial cognitive impairment, which was accompanied by insufficient histone acetylation of the H4K12-specific lysine residue and repressed c-Fos gene expression immediately after acquisition training. Moreover, the enrichment of acetyl-H4K12 on the c-Fos promoter following acquisition training was decreased in LPS-treated mice. Administration of trichostatin A (TSA), a histone deacetylase inhibitor, 2 h before each MWM acquisition training session effectively enhanced hippocampal histone acetylation levels and enrichment of acetyl-H4K12 on the c-Fos promoter following acquisition training in LPS-treated mice. TSA also increased c-Fos gene expression underlying synaptic plasticity and memory formation, and consequently rescued impaired spatial cognitive function. These results indicate that the dysregulation of H4K12 acetylation during the ongoing process of memory formation plays a key role in the spatial cognitive impairment associated with a neonatal LPS challenge. The histone deacetylase inhibitor TSA exhibits therapeutic potential for treating cognitive impairment induced by neonatal inflammation, by means of improving hippocampal histone acetylation and downstream c-Fos gene expression in response to a learning task.

Maternal Epidural Steroids to Prevent Neonatal Exposure to Hyperthermia and Inflammation.

Epidural analgesia is associated with a fourfold increased rate of intrapartum fever. The likely pathophysiology is a noninfectious maternal inflammatory activation. Safe interventions to reduce maternal and neonatal exposures to intrapartum fever and inflammation are needed. The purpose of this study was to determine if prophylactic epidural steroids decrease fetal exposure to hyperthermia and inflammatory cytokines following epidural analgesia. This is a randomized, double-blinded, placebo controlled trial. Term nulliparous women requesting epidural analgesia received 80 mg methylprednisolone or preservative-free normal saline via the epidural catheter at placement. The primary outcome was maternal temperature >100.4°F. Secondary outcomes included fetal exposure to inflammation as assessed by cord blood interleukin-6 (IL-6) levels and rates of funisitis. Power analysis estimated a sample size requirement of 276, but new Food and Drug Administration (FDA) recommendations advising a black box warning on epidural steroids resulted in early study termination. A total of 116 subjects were enrolled: 58 treatments and 58 placebos. There was no difference in the rate of maternal intrapartum fever or cord blood IL-6 levels between treatment arms. No complications listed in the FDA warning occurred. Prophylactic epidural methylprednisolone was not effective in reducing intrapartum fever or neonatal inflammation following epidural analgesia. Alternate mechanisms and preventative strategies should be considered.

256 - Neonatal systemic inflammation: long term evaluation of mortality, body mass, expression of TNF-α and production of oxidative stress in the cerebellum

The central nervous system is especially vulnerable in the neonatal period. Inflammatory processes occurring in this moment of life may affect its normal development. To evaluate the long term effects of a systemic inflammatory process induced by lipopolysaccharide (LPS) injection during the neonatal period. Neonatal rats (Wistar, male) were randomly assigned to three different groups: NAIVE (n=9), Saline (SAL) (n=8) and LPS (n=11). Solutions were systemically injected (i.p.) on pos-natal (P) days P1, P3, P5 and P7. Body mass was verified at different time points. Rats were euthanized at P89. The cerebellum of some rats were freshly dissected and the mRNA expression of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF- α) was analyzed using qPCR. Subsets of rats were perfused and the oxidative stress level in the cerebellum was assessed with dihydroetidine (DHE). Animals injected with LPS presented a higher mortality rate on the first week of life as compared to other groups (NAIVE 31%, SAL 20%, LPS 73%, p

259 - LPS-induced systemic neonatal inflammation: blockage of P2X7R by BBG on neonatal phase decreases oxidative stress in hippocampus of adult rats

The neonatal period is marked by intense maturation of the immune and central nervous systems and the exposure to inflammation during this phase of life may produce long-term effects on the neural system. Here, we examined the impact of neonatal lipopolysaccharide (LPS) exposure on anxiety and pain sensitivity, as well as the superoxide production in adult rats. We also assessed if the blockage of the P2X7R by its antagonist BBG could modulate the effects of LPS on the central nervous system. Wistar male rats were injected with saline (0.9% solution), LPS (1mg/kg, Escherichia coli) or LPS and BBG (50mg/Kg) on postnatal days (PNDs) 1, 3, 5 and 7. Anxiety was evaluated in the Elevated Plus Maze test and nociception in the Hot Plate and Tail Flick tests during adulthood at PNDs 80, 82 and 84 respectively. At PND89, euthanasia was performed and the brain collected for measuring superoxide levels by Dihydroethidium (DHE). No statistical differences were found in Elevated plus maze, Hot-plate nor Tail-flick tests. However, the persistent systemic neonatal inflammation lead to a higher production of superoxide anion in the hippocampus and the blockage of the P2X7R decreased its production (p

Effect of early-life inflammation and magnesium sulfate on hyperthermia-induced seizures in infant rats: Susceptibility to pentylenetetrazol-induced seizures later in life.

This study investigated the effect of inflammation and MgSO4 pretreatment on behaviors caused by hyperthermia (HT) and the effect of these interventions on PTZ-induced seizure a week later. In this experimental study, rat pups experienced inflammation on postnatal day 10 (P10). On P18-19, the pups received either saline or MgSO4 then subjected to hyperthermia. On P25-26, PTZ-induced seizure was initiated in the rats. Neonatal inflammation increased the susceptibility to HT-induced seizure. Inflammation and HT increased the susceptibility to PTZ-induced seizure. Pretreatment with MgSO4 before hyperthermia decreased the susceptibility to both HT- and PTZ-induced seizure. Furthermore, calcium and magnesium blood levels significantly decreased compared to control rats. It can be concluded that neonatal inflammation potentiates while pretreatment with MgSO4 attenuates HT-induced seizures. Also, neonatal inflammation and HT potentiate PTZ-induced seizure initiated one week later.

Sustained Neonatal Inflammation Is Associated with Poor Growth in Infants Born Very Preterm during the First Year of Life

To determine whether a sustained neonatal systemic inflammatory response was associated with poor postnatal growth among infants born very preterm during the first year of life. We studied prospectively 192 infants born preterm (birth weight ≤1.5 kg and gestational age ≤31 weeks). Weight, length, and head circumference were measured at birth, term, 4, and 12 months of corrected age. Serial C-reactive protein and procalcitonin were measured at 1, 3, 7, 14, and 28 days of age and averaged for each infant. A sustained neonatal systemic inflammatory response was defined as an average C-reactive protein level greater than the median for the group. Analysis was undertaken with linear mixed models. Decreases in mean z scores for weight, length, and head circumference were associated with the presence of a sustained neonatal systemic inflammatory response from birth to 12 months of corrected age (β [95% CI] = -0.282 [-0.306 to -0.258]; -1.899 [-2.028,-1.769]; -0.806 [-0.910, to -0.701], P < .001, respectively) in main effect models. This association remained significant after including interaction terms for bronchopulmonary dysplasia, neonatal sepsis, and necrotizing enterocolitis (β [95% CI] = -0.393 [-0.520 to -0.265]; -2.128 [-2.754, -1.503]; -1.102 [-1.604, -0.600]; P < .001; respectively) in interaction models. A sustained neonatal systemic inflammatory response was associated with poor postnatal growth, particularly poor linear growth. Serial C-reactive protein and procalcitonin may be useful markers for identifying infants at risk for postnatal growth failure.

Spinal mechanisms of pudendal nerve stimulation-induced inhibition of bladder hypersensitivity in rats

Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models of bladder pain and anecdotally reduces pain in humans with pelvic pain of urologic origin. The spinal neurochemical mechanisms of this antinociception are unknown. In the present study, bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Visceromotor responses (VMRs; abdominal muscle contractions) to urinary bladder distension (UBD) were used as a nociceptive endpoint under urethane-isoflurane anesthesia. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Following determination of the inhibitory effect of bPNS on VMRs, pharmacological antagonists were administered via an intrathecal catheter onto the lumbosacral spinal cord and bPNS effects on VMRs redetermined. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that was statistically reduced by the intrathecal administration of methysergide, WAY100636, CGP35348 and strychnine but was unaffected by naloxone, bicuculline, phentolamine, ondansetron and normal saline. This study suggests that inhibitory effects of bPNS may include serotonergic, GABA-B-ergic and glycinergic mechanisms suggesting the potential for interaction of the neuromodulatory effect with concommitant drug therapies.

Neonatal bladder inflammation alters the role of the central amygdala in hypersensitivity produced by Acute Footshock stress in adult female rats

There is increasing evidence that chronic pain may be associated with events that occur during critical periods of development. Recent studies have identified behavioral, spinal neurophysiological and spinal/peripheral neurochemical differences in rats that have experienced neonatal bladder inflammation (NBI): a putative model of the chronically painful bladder disorder, interstitial cystitis. Stress has been shown to exacerbate symptoms of interstitial cystitis and produces bladder hypersensitivity in animal models. We recently reported that Acute Footshock-induced bladder hypersensitivity was eliminated in otherwise normal rats by prior bilateral lesions of the central nucleus of the amygdala. Since the spinal and peripheral nervous systems of NBI-treated rats are known to differ from normal rats, the present experiments sought to determine whether a supraspinal nervous system structure, the central amygdala, is still necessary for the induction of Acute Footshock-induced hypersensitivity. The effect of bilateral amygdala electrolytic lesions on Acute Footshock-induced bladder hypersensitivity in adult female rats was tested in Control rats which underwent a control protocol as neonates and in experimental rats which experienced NBI. Consistent with our previous report, in Control rats, Acute Footshock-induced bladder hypersensitivity was eliminated by bilateral Amygdala Lesions. In contrast, Acute Footshock-induced bladder hypersensitivity in NBI-treated rats was unaffected by bilateral Amygdala Lesions. These findings provide evidence that NBI results in the recruitment of substrates of bladder hypersensitivity that may differ from those of normal rats. This, in turn, suggests that unique therapeutics may be needed for painful bladder disorders like interstitial cystitis.

Perfusion Index: A Noninvasive Tool for Clinical Decision in Neonates with Suspected Sepsis?

Aim This article aims to assess whether perfusion index is significantly different in infants with positive C-reactive protein and/or positive cultures compared with a control group. Methods This was a prospective observational cohort study. Perfusion index was evaluated in 80 neonates at the start of antibiotic therapy for suspected sepsis. Antibiotic therapy was started based on the antenatal history or the presence of clinical signs of sepsis such as hypo/hyperthermia, feed intolerance, lethargy, hypotonia, irregular cardiac rhythms, bradycardia, cyanosis, apnea, respiratory distress, and metabolic acidosis. A case group of 23 neonates with abnormal C- reactive protein (&gt; 10 mg/L) and/or positive cultures (blood, liquor, or bronchoalveolar lavage cultures) was compared with a control group of 23 neonates. Results Cases (mean gestational age [GA], 33 ± 5) and controls (mean GA, 33 ± 5) were matched according to the following criteria: GA (±2 weeks), postmenstrual age (±2 weeks), early (&lt; 72 hours), or late (&gt; 72 hours) onset of suspected infection. Mean perfusion index was 0.8 ± 0.3 in the case group and 1.2 ± 0.4 in the control group; p-value of &lt; 0.001. Conclusions Perfusion index can be considered a noninvasive, reproducible, and easy-to-apply tool for early diagnosis of a neonatal acute inflammation in course of sepsis.

1084 - Neonatal Colonic Inflammation Aggravates Epithelial Injury Through Mir-196 When Exposed to Another Episode of Inflammation in Adult-Life

1084 - Neonatal Colonic Inflammation Aggravates Epithelial Injury Through Mir-196 When Exposed to Another Episode of Inflammation in Adult-Life

Neonatal inflammation induces reorganization in dendritic morphology of retinal ganglion cells but not their retinogeniculate projection in mice

Perinatal inflammatory insult in preterm babies is associated with vision impairment, but the underlying cellular mechanism is still unknown. In this study, we set out to explore whether systemic inflammatory stress affects the development of retinal ganglion cells (RGCs). Neonatal inflammation was induced by single and systemic injection of lipopolysaccharide (LPS, 1 mg/kg) at postnatal day 4 (P4). Morphological changes of RGCs were investigated by using 3D neuron reconstruction technique in Thy-1 YFPH transgenic mice at P21, of which a fraction of RGCs selectively expresses the yellow fluorescent protein (YFP). Three types (Type I, II, III) of RGCs were distinguished and classified according to the characteristic features in their dendritic field area and dendrite density. Neonatal exposure to LPS did not alter the composition of the three RGC types but induced a reorganization of dendritic architecture in the RGC Type I and II (but not Type III). The average diameter, surface area and volume of dendrites in both RGC Type I and II were increased after systemic inflammation compared with those in the control group. However, soma sizes of all three RGC types were not affected by neonatal inflammation. Meanwhile, using anterograde labeling of the retinal cells, we found that neonatal exposure to LPS also did not affect the pattern of RGC projections in the dorsal lateral geniculate nucleus of the thalamus (dLGN). These results indicate that RGC dendrite reorganization induced by neonatal inflammation may contribute to the retinal cell dysfunctions associated with systemic inflammation in premature babies.

Neonatal Inflammation Impairs Multiple Pathways to Adult Respiratory Plasticity

Bacterial‐induced inflammation is a common clinical problem in neonates and acutely impairs respiratory control, but we know little about the long‐term effects of neonatal inflammation on adult respiratory control. Since neonatal inflammation blunts adult immune function, reduces adult hippocampal plasticity, and increases the vulnerability to neuropsychiatric disorders, we hypothesized that neonatal systemic inflammation would inhibit adult phrenic long‐term facilitation (pLTF), a form of respiratory neuroplasticity induced by acute intermittent hypoxia (AIH). pLTF can be induced by distinct cellular mechanisms including the Q‐pathway, induced by moderate AIH (PaO2 35–45 mmHg), and the S‐pathway, induced by severe AIH (PaO2 25–35 mmHg). Therefore, we tested the hypothesis that neonatal inflammation would undermine both the Q‐ and S‐pathway to pLTF. Postnatal day 4 (P4) pups of both sexes were injected with either lipopolysaccharide (LPS; 1 mg/kg) or sterile saline and allowed to mature to adulthood. In order to control the known effects of estrus cycle hormones on pLTF, adult females were ovariectomized 7–8 days prior and given 17‐β estradiol (40 μg/ml/kg, 3 hours) before AIH. Neonatal LPS undermined adult mAIH‐induced (Q‐pathway) pLTF in both females (−15 ± 17%, n=6, p &lt; 0.0001) and males (14 ± 14%, n=12, p = 0.01) relative to neonatal Saline controls (females; 97 ± 24%, n=7, males; 55 ± 13%, n=7). Acute, adult treatment with a systemic anti‐inflammatory (ketoprofen, 12.5 mg/ml/kg, i.p., 3 hours) restored Q‐pathway pLTF after neonatal LPS in both females (118 ± 24%, n=4) and males (58 ± 9%, n=4) to saline controls treated with ketoprofen (P4 Saline females; 67 ± 11%, n=4, males; 54 ± 9%, n=4). Additionally, sAIH‐induced (S‐pathway) pLTF was undermined in adults after neonatal LPS in females (0 ± 17%, n=4, p &lt; 0.001) and males (7 ± 9%, n=4, p &lt; 0.01) compared to neonatal saline control females (86 ± 23%, n=4) and males (47 ± 17%, n=4). However, systemic ketoprofen in adults did not restore S‐pathway pLTF after neonatal inflammation in females (P4 Saline; 136 ± 11%, n=4, P4 LPS; 23 ± 15%, n=5, p &lt; 0.0001) or males (P4 Saline; 67 ± 11%, n=4, P4 LPS; −5 ± 37%, n=4, p &lt; 0.01). Thus, neonatal systemic inflammation has a lasting effect of respiratory plasticity by abolishing multiple pathways to adult respiratory plasticity. Furthermore, the restoration of Q‐pathway, but not S‐pathway, mediated plasticity by acute ketoprofen demonstrates different mechanisms impair adult respiratory plasticity after neonatal inflammation. Understanding how neonatal inflammation impairs the adult respiratory system will elucidate links between neonatal conditions and adult respiratory insufficiency, leading to better therapies to enhance breathing in all age groups.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Maternal high fructose diet and neonatal immune challenge alter offspring anxiety-like behavior and inflammation across the lifespan

AimsThis study examined the interaction between maternal high fructose diet and neonatal inflammation in neonates (P7), juveniles (P26–34) and adults on measures of anxiety-like behavior and cognition. The study aimed to assess the potential synergistic effects of these two forms of early-life inflammation. Main methodsWe fed Sprague-Dawley dams with high fructose (60%) diet or normal chow. Each litter was treated with either saline or lipopolysaccharide (LPS) on postnatal day (P)3 and P5 and two pups were tested for USVs after maternal separation on P7. Post-weaning, juveniles were tested on the elevated zero maze (EZM) and in a context-object discrimination (COD) task prior to tissue harvest. Adults were tested on the EZM and the COD task as well. Immunohistochemistry and ELISA were used to assess molecular and cellular changes in the offspring. Key findingsThis study demonstrates that maternal diet and neonatal inflammation altered peripheral inflammation in neonates, altered anxiety-like behavior in juveniles, and altered anxiety-like behavior in adulthood. Maternal diet and sex increased juvenile peripheral inflammation and altered memory on the context-discrimination task. SignificanceMaternal diet has a profound impact on fetal and neonatal development, especially as obesity rates are on the rise worldwide. Together, these findings reveal enduring effects of maternal diet on offspring, support the findings on the effects of neonatal inflammation on anxiety-like behaviors in later-life periods, and add to the complex relationship between gestational and neonatal inflammation and anxiety.

Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm

BackgroundDifficulties with reading and math occur more commonly among children born extremely preterm than among children born at term. Reasons for this are unclear. MethodsWe measured the concentrations of 27 inflammatory-related and neurotrophic/angiogenic proteins (angio-neurotrophic proteins) in multiple blood specimens collected a week apart during the first postnatal month from 660 children born before the 28th week of gestation who at age 10 years had an IQ ≥ 70 and a Wechsler Individual Achievement Test 3rd edition (WIAT-III) assessment. We identified four groups of children, those who had a Z-score ≤ −1 on the Word Reading assessment only, on the Numerical Operations assessment only, on both of these assessments, and on neither, which served as the referent group. We then modeled the risk of each learning limitation associated with a top quartile concentration of each protein, and with high and lower concentrations of multiple proteins. ResultsThe protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio-neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-α in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins. ConclusionsHigh concentrations of angio-neurotrophic proteins appear to reduce/moderate the risk of each learning limitation associated with systemic inflammation. The three categories of limitations have protein profiles with some similarities, and yet some differences, too.

Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature.

BackgroundChildhood obesity is associated with elevated blood concentrations of inflammation markers. It is not known to what extent inflammation precedes the development of obesity.MethodsIn a cohort of 882 infants born before 28 weeks of gestation, we examined relationships between concentrations of 25 inflammation-related proteins in blood obtained during the first two postnatal weeks and body mass index at 2 years of age.ResultsAmong children delivered for spontaneous indications (n=734), obesity was associated with elevated concentrations of four proteins (IL-1β, IL-6, TNF-R1, and MCP-1) on the first postnatal day; one protein (IL-6) on postnatal day 7; and two proteins (ICAM-3 and VEGF-R1) on postnatal day 14. Among children delivered for maternal or fetal indications (n=148), obesity was associated with elevated concentrations of seven proteins on the 14th postnatal day. In multivariable models in the spontaneous indications subsample, elevated IL-6 on day 1 predicted obesity (odds ratio: 2.9; 95% confidence limits: 1.2, 6.8), while elevated VCAM-1 on day 14 predicted overweight at 2 years of age (odds ratio: 2.3; 95% confidence limits: 1.2, 4.3).ConclusionsIn this cohort, neonatal systemic inflammation preceded the onset of obesity, suggesting that inflammation might contribute to the development of obesity.

Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life.

Background & AimsEarly life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β.MethodsWe developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid.ResultsAggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1–derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol.ConclusionsNI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.

Neonatal Colonic Inflammation Increases Spinal Transmission and Cystathionine β-Synthetase Expression in Spinal Dorsal Horn of Rats with Visceral Hypersensitivity.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and alteration of bowel movements. The pathogenesis of visceral hypersensitivity in IBS patients remains largely unknown. Hydrogen sulfide (H2S) is reported to play an important role in development of visceral hyperalgesia. However, the role of H2S at spinal dorsal horn level remains elusive in visceral hypersensitivity. The aim of this study is designed to investigate how H2S takes part in visceral hypersensitivity of adult rats with neonatal colonic inflammation (NCI). Visceral hypersensitivity was induced by neonatal colonic injection of diluted acetic acid. Expression of an endogenous H2S synthesizing enzyme cystathionine β-synthetase (CBS) was determined by Western blot. Excitability and synaptic transmission of neurons in the substantia gelatinosa (SG) of spinal cord was recorded by patch clamping. Here, we showed that expression of CBS in the spinal dorsal horn was significantly upregulated in NCI rats. The frequency of glutamatergic synaptic activities in SG was markedly enhanced in NCI rats when compared with control rats. Application of NaHS increased the frequency of both spontaneous and miniature excitatory post-synaptic currents of SG neurons in control rats through a presynaptic mechanism. In contrast, application of AOAA, an inhibitor of CBS, dramatically suppressed the frequency of glutamatergic synaptic activities of SG neurons of NCI rats. Importantly, intrathecal injection of AOAA remarkably attenuated visceral hypersensitivity of NCI rats. These results suggest that H2S modulates pain signaling likely through a presynaptic mechanism in SG of spinal dorsal horn, thus providing a potential therapeutic strategy for treatment for chronic visceral pain in patients with IBS.