- Email: [email protected]
P2-45 Exposure to repeated intraamniotic endotoxin causes pulmonary and systemic endotoxin tolerance in the preterm sheep fetus
Posters
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glucose tolerance, whereas strong weight growth throughout childhood was associated with protection (chi-sq = 12.73, df = 4, p = 0.01). By regression of the GTT score upon the probabilistic assignment to clusters, the statistical evidence is emphasized [F (4,603) = 5.28, p < 0.0005). Conclusions: Evidence that poor childhood development is associated with impaired glucose tolerance has been revealed by examining the natural clustering of weight trajectories. This approach avoids issues of collinearity that would be evident if the health outcome were regressed upon multiple childhood weights.
(P = 0.024). There was no effect of diet at any other time point on thymus or spleen weight in males or females. Conclusions: There may be an effect of gender on short-term susceptibility to foetal programming of thymus weight. However, there does not appear to be any lasting effect on the offspring of altering balance of n-3 and n-6 PUFAs in pregnancy on spleen or thymus weight. Further analysis is required to determine the relative abundance of different immune cells and T-cell responses in lymphoid organs, and whether these parameters are affected by gender.
P2-43 Birth weight and risk of type 2 diabetes: a quantitative systematic review of published evidence
P2-45 Exposure to repeated intraamniotic endotoxin causes pulmonary and systemic endotoxin tolerance in the preterm sheep fetus
P.H. Whincup1 *, S. Kaye1 , C.G. Owen1 , R. Huxley2 , D.G. Cook1 , for the EARLYREAD (Early Risk Exposures in Adult Disease) Collaboration. 1 Division of Community Health Sciences, St George’s, University of London, UK, 2 George Institute, University of Sydney, Australia E-mail: [email protected] Aim: To review published evidence relating birth weight and type 2 diabetes (T2DM). Study design: Systematic review and meta-analysis of published studies relating birth weight and T2DM in adults. Subjects: Data were available for 31 of 32 relevant studies (6,172 cases, 208,464 individuals, 32 populations). Outcome measures: Relative risk of T2DM associated with a 1 kg increase in birth weight. Where possible, the effects of adjustment (body mass index, social class) and exclusion (macrosomia, maternal diabetes) were examined. Results: There was considerable heterogeneity between studies (c231 = 89.6, p < 0.0001) largely due to positive birth weightT2DM associations in 3 populations with high rates of maternal diabetes and/or macrosomia. The remaining studies showed little heterogeneity (c228 = 33.9, p = 0.21) and a graded inverse association between birth weight and T2DM (pooled age and sex adjusted relative risk 0.78, 95% CI 0.74 0.82 per kg), with no evidence of publication bias. Among these studies, the association was strengthened by approximately one third by adjustment for BMI or the exclusion of macrosomic infants and was unaffected by social class adjustment. The proportional reduction in T2DM incidence predicted from an SD increase in birth weight (0.58 kg) was 13% (95% CI 11 16%), increasing to 16% (95% CI 13 0%) after the exclusion of macrosomic infants. Conclusions: In most populations studied, lower birth weight was independently related to an increased risk of T2DM. However, the potential for reducing T2DM incidence by interventions increasing birth weight appears likely to be limited. P2-44 Maternal fatty acid intake in pregnancy may affect lymphoid organ development of offspring in a gender-specific manner A.L. Fear *, P.C. Calder. Institute of Developmental Sciences & Institute of Human Nutrition, University of Southampton, UK E-mail: [email protected] Aims: The study aimed to determine whether altered maternal fatty acid intake during gestation in the rat affects immune status of male or female offspring post-parturition, and if so, whether this change is maintained into adulthood. Subjects: 12 ten-week old nulliparous Wistar rats. Study design: Following conception, dams were randomised into one of two dietary groups. The diets contained salmon oil (rich in n-3 PUFAs) or sunflower oil (rich in n-6 PUFAs). At birth, litters were reduced to 8 pups and dams received a standard chow diet. Pups were weaned onto chow at 3 weeks of age. Outcome measures: Spleen and thymus weights were measured in offspring at 3, 6, 9 and 12 weeks of age. Results: At 3 weeks, females in the salmon oil group had significantly heavier thymuses than those in the sunflower oil group
S. Kallapur *. Cincinnati Childrens Hospital, USA Background: The occurrence of chorioamnionitis (inflammation of the fetal membranes) induced bronchopulmonary dysplasia (BPD) is variable in preterm infants. Chorioamnionitis induced in the pre-term sheep fetuses by one injection of intra-amniotic (IA) endotoxin (Endo) results in lung injury responses resembling BPD, but repeated exposures to IA Endo do not result in a persistent lung injury response. Hypothesis: Repeated exposure to IA Endo induces endotoxin tolerance. Design and Methods: IA saline (control) or E. coli lipopolysaccharide O55:B5 (10 mg) (LPS) was given either 2d (2d group), 7d (7d group) or 2&7d (2+7d group) prior to preterm delivery at 125 d gestation (Term = 150d). Responses to endotoxin were measured in vivo (lung IL-1b, liver serum amyloid A3 mRNA) or in vitro (lung, blood monocyte production of IL-6 in response to 100 ng/ml LPS for 16 h. Results: See the figure.
Conclusions: Prior exposure of endotoxin decreased in vivo and in vitro lung and systemic endo responsiveness, consistent with endotoxin tolerance. Speculation: Endotoxin tolerance may be one mechanism by which a preterm infant may have relative protection to lung injury in the face of prolonged or repeat exposures to antenatal inflammation. Fetal endotoxin tolerance may modulate postnatal innate immune responses. Funded by NIH K08 HL70711, HD12714, HL65397, NHRMC. P2-46 Multiple pro-inflammatory signalling pathways are affected when fetal immune modulation is induced by repetitive intra-amniotic endotoxin injection in sheep B.W. Kramer1 *, S.G. Kallapur2 , I. Nitsos3 , T.J.M. Moss3 , J.P. Newnham3 , A.H. Jobe2 . 1 University Hospital Maastricht, Maastricht, The Netherlands, 2 Cincinnati Children’s Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio, USA, 3 School of Women’s and Infants‘ Health, University of Western Australia, Perth, Australia Background: Intra-uterine exposure to antigens may affect fetal and postnatal immune responses. Intra-amniotic injection of endotoxin in pregnant sheep, induced chorioamnionitis, inflammation in the fetal lung, a modest systemic inflammation, and endotoxin tolerance in fetal blood monocytes. Hypothesis: Chorioamnionitis-induced immunomodulation affects the responses to other Toll-like receptor (TLR) ligands, such as flagellin (TLR5) and double-stranded (ds) RNA (TLR3). Methods: Time-mated ewes with singletons were assigned to groups of 5 7 animals to undergo ultrasound-guided intra-amniotic injection of endotoxin (10 mg, E. coli 055:B5) or saline. Responses
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glucose tolerance, whereas strong weight growth throughout childhood was associated with protection (chi-sq = 12.73, df = 4, p = 0.01). By regression of the GTT score upon the probabilistic assignment to clusters, the statistical evidence is emphasized [F (4,603) = 5.28, p < 0.0005). Conclusions: Evidence that poor childhood development is associated with impaired glucose tolerance has been revealed by examining the natural clustering of weight trajectories. This approach avoids issues of collinearity that would be evident if the health outcome were regressed upon multiple childhood weights.
(P = 0.024). There was no effect of diet at any other time point on thymus or spleen weight in males or females. Conclusions: There may be an effect of gender on short-term susceptibility to foetal programming of thymus weight. However, there does not appear to be any lasting effect on the offspring of altering balance of n-3 and n-6 PUFAs in pregnancy on spleen or thymus weight. Further analysis is required to determine the relative abundance of different immune cells and T-cell responses in lymphoid organs, and whether these parameters are affected by gender.
P2-43 Birth weight and risk of type 2 diabetes: a quantitative systematic review of published evidence
P2-45 Exposure to repeated intraamniotic endotoxin causes pulmonary and systemic endotoxin tolerance in the preterm sheep fetus
P.H. Whincup1 *, S. Kaye1 , C.G. Owen1 , R. Huxley2 , D.G. Cook1 , for the EARLYREAD (Early Risk Exposures in Adult Disease) Collaboration. 1 Division of Community Health Sciences, St George’s, University of London, UK, 2 George Institute, University of Sydney, Australia E-mail: [email protected] Aim: To review published evidence relating birth weight and type 2 diabetes (T2DM). Study design: Systematic review and meta-analysis of published studies relating birth weight and T2DM in adults. Subjects: Data were available for 31 of 32 relevant studies (6,172 cases, 208,464 individuals, 32 populations). Outcome measures: Relative risk of T2DM associated with a 1 kg increase in birth weight. Where possible, the effects of adjustment (body mass index, social class) and exclusion (macrosomia, maternal diabetes) were examined. Results: There was considerable heterogeneity between studies (c231 = 89.6, p < 0.0001) largely due to positive birth weightT2DM associations in 3 populations with high rates of maternal diabetes and/or macrosomia. The remaining studies showed little heterogeneity (c228 = 33.9, p = 0.21) and a graded inverse association between birth weight and T2DM (pooled age and sex adjusted relative risk 0.78, 95% CI 0.74 0.82 per kg), with no evidence of publication bias. Among these studies, the association was strengthened by approximately one third by adjustment for BMI or the exclusion of macrosomic infants and was unaffected by social class adjustment. The proportional reduction in T2DM incidence predicted from an SD increase in birth weight (0.58 kg) was 13% (95% CI 11 16%), increasing to 16% (95% CI 13 0%) after the exclusion of macrosomic infants. Conclusions: In most populations studied, lower birth weight was independently related to an increased risk of T2DM. However, the potential for reducing T2DM incidence by interventions increasing birth weight appears likely to be limited. P2-44 Maternal fatty acid intake in pregnancy may affect lymphoid organ development of offspring in a gender-specific manner A.L. Fear *, P.C. Calder. Institute of Developmental Sciences & Institute of Human Nutrition, University of Southampton, UK E-mail: [email protected] Aims: The study aimed to determine whether altered maternal fatty acid intake during gestation in the rat affects immune status of male or female offspring post-parturition, and if so, whether this change is maintained into adulthood. Subjects: 12 ten-week old nulliparous Wistar rats. Study design: Following conception, dams were randomised into one of two dietary groups. The diets contained salmon oil (rich in n-3 PUFAs) or sunflower oil (rich in n-6 PUFAs). At birth, litters were reduced to 8 pups and dams received a standard chow diet. Pups were weaned onto chow at 3 weeks of age. Outcome measures: Spleen and thymus weights were measured in offspring at 3, 6, 9 and 12 weeks of age. Results: At 3 weeks, females in the salmon oil group had significantly heavier thymuses than those in the sunflower oil group
S. Kallapur *. Cincinnati Childrens Hospital, USA Background: The occurrence of chorioamnionitis (inflammation of the fetal membranes) induced bronchopulmonary dysplasia (BPD) is variable in preterm infants. Chorioamnionitis induced in the pre-term sheep fetuses by one injection of intra-amniotic (IA) endotoxin (Endo) results in lung injury responses resembling BPD, but repeated exposures to IA Endo do not result in a persistent lung injury response. Hypothesis: Repeated exposure to IA Endo induces endotoxin tolerance. Design and Methods: IA saline (control) or E. coli lipopolysaccharide O55:B5 (10 mg) (LPS) was given either 2d (2d group), 7d (7d group) or 2&7d (2+7d group) prior to preterm delivery at 125 d gestation (Term = 150d). Responses to endotoxin were measured in vivo (lung IL-1b, liver serum amyloid A3 mRNA) or in vitro (lung, blood monocyte production of IL-6 in response to 100 ng/ml LPS for 16 h. Results: See the figure.
Conclusions: Prior exposure of endotoxin decreased in vivo and in vitro lung and systemic endo responsiveness, consistent with endotoxin tolerance. Speculation: Endotoxin tolerance may be one mechanism by which a preterm infant may have relative protection to lung injury in the face of prolonged or repeat exposures to antenatal inflammation. Fetal endotoxin tolerance may modulate postnatal innate immune responses. Funded by NIH K08 HL70711, HD12714, HL65397, NHRMC. P2-46 Multiple pro-inflammatory signalling pathways are affected when fetal immune modulation is induced by repetitive intra-amniotic endotoxin injection in sheep B.W. Kramer1 *, S.G. Kallapur2 , I. Nitsos3 , T.J.M. Moss3 , J.P. Newnham3 , A.H. Jobe2 . 1 University Hospital Maastricht, Maastricht, The Netherlands, 2 Cincinnati Children’s Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio, USA, 3 School of Women’s and Infants‘ Health, University of Western Australia, Perth, Australia Background: Intra-uterine exposure to antigens may affect fetal and postnatal immune responses. Intra-amniotic injection of endotoxin in pregnant sheep, induced chorioamnionitis, inflammation in the fetal lung, a modest systemic inflammation, and endotoxin tolerance in fetal blood monocytes. Hypothesis: Chorioamnionitis-induced immunomodulation affects the responses to other Toll-like receptor (TLR) ligands, such as flagellin (TLR5) and double-stranded (ds) RNA (TLR3). Methods: Time-mated ewes with singletons were assigned to groups of 5 7 animals to undergo ultrasound-guided intra-amniotic injection of endotoxin (10 mg, E. coli 055:B5) or saline. Responses