Fetal glucocorticoid-regulated pathways are not affected by inhaled corticosteroid use for asthma during pregnancy.

RATIONALE: Inhaled corticosteroids (ICS) are currently advised for the control of asthma during pregnancy, despite the lack of evidence regarding potential systemic effects on maternal, placental, and fetal systems. OBJECTIVES: To determine maternal plasma concentrations of cortisol, estriol, osteocalcin, and corticotropin-releasing hormone in pregnant women with asthma (n = 156) and without asthma (n = 51). METHODS: During each trimester of pregnancy, the use and dose of ICS was recorded and blood samples were collected. Ultrasound was performed at 18 and 30 weeks' gestation, and birth weight and fetal sex were recorded at delivery. MEASUREMENTS AND MAIN RESULTS: Maternal hormone concentrations were not affected by the presence of asthma; however, they were inhibited by ICS use in a dose-dependent manner. This was dependent on fetal sex: in pregnancies with a female, ICS was inversely associated with maternal cortisol in first trimester and inversely associated with maternal osteocalcin in second and third trimester. When pregnant with a male, no effect of ICS dose was observed on maternal cortisol, estriol, or osteocalcin levels, whereas corticotropin-releasing hormone levels were increased with ICS use only in the first trimester. CONCLUSIONS: Maternal glucocorticoid-regulated systems appeared susceptible to ICS only when pregnant with a female. Fetal adrenal function appeared unaffected by ICS in pregnancies of both males and females. This provides clinically important information suggesting that ICS do not exert effects on glucocorticoid-regulated pathways in the fetus, and therefore are unlikely to contribute to adverse effects on fetal growth and development.

Placental cytokine expression covaries with maternal asthma severity and fetal sex.

In the presence of maternal asthma, we have previously reported reduced placental blood flow, decreased cortisol metabolism, and reductions in fetal growth in response to maternal asthma and asthma exacerbations. We have proposed that these changes in placental function and fetal development may be related to activation of proinflammatory pathways in the placenta in response to maternal asthma. In the present study, we examined the influence of maternal asthma severity, inhaled glucocorticoid treatment, maternal cigarette use, placental macrophage numbers, and fetal sex on placental cytokine mRNA expression from a prospective cohort study of pregnant women with and without asthma. Placental expression of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-5 mRNA were all increased significantly in placentae of female fetuses whose mothers had mild asthma, but no changes were observed in placentae of male fetuses. The proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were negatively correlated with female cord blood cortisol, but there were no such correlations in placentae from males. Multivariate analysis indicated the strongest predictor of both cytokine mRNA expression in the placenta and birth weight was fetal cortisol but only in females. Placental cytokine mRNA levels were not significantly altered by inhaled glucocorticoid use, placental macrophage numbers, cigarette use, moderate-severe asthma, or male sex. These data suggest that placental basal cytokine mRNA expression is sex specifically regulated in pregnancies complicated by asthma, and interestingly these changes are more prevalent in mild rather than severe asthma.

Sex-specific associations between cortisol and birth weight in pregnancies complicated by asthma are not due to differential glucocorticoid receptor expression.

BACKGROUND: Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and has long-term consequences for adult health. Sex-specific fetal growth patterns are observed in pregnancies with maternal asthma and may be due to differential sensitivity of the placenta to glucocorticoids. It is currently unknown whether expression of the placental glucocorticoid receptor (GR) becomes altered with asthma or the use of inhaled corticosteroids. METHODS: Pregnant women with mild asthma (n=52), moderate-severe asthma (n=71) and without asthma (n=51) were recruited at John Hunter Hospital, Newcastle, Australia. At delivery, placentae and cord blood were collected, and fetal sex and birth weight were recorded. Placental GR heterogeneous nuclear RNA (hnRNA), mRNA and protein were measured and cord blood cortisol concentrations were assessed. RESULTS: Placental GR gene activity increased with cortisol exposure but decreased with inhaled corticosteroid treatment (p=0.05). With maternal asthma, female birth weight centiles were inversely associated with cortisol (r=-0.286, p=0.017) and, despite a decrease in placental GR mRNA (p=0.003), placental GRalpha protein levels were unchanged. In males, no change to cortisol, birth weight or placental GR were evident in pregnancies with asthma. Together, these results indicate that in pregnancies complicated by asthma, placental GR gene activity, but not mRNA expression or protein levels, is dependent on cortisol and inhaled corticosteroid treatment. CONCLUSIONS: The sex-specific associations between cortisol and birth weight observed in pregnancies with asthma are not due to altered GR expression; however, they may be due to differential glucocorticoid sensitivity via preferential transcription of GR isoforms or post-translational modifications.

Asthma during pregnancy alters immune cell profile and airway epithelial chemokine release.

OBJECTIVE: Pregnancy can influence the course of maternal asthma, but the mechanisms are presently unknown. The aim of the present study was to access maternal immune cell profiles in the presence and absence of asthma and to determine the effect of pregnancy-derived factors on epithelial cell function. METHODS: Cells from the human bronchial epithelial cell line BEAS-2B were treated with plasma from pregnant or nonpregnant asthmatic and nonasthmatic subjects. Cell culture supernatants were collected after 24 h and assayed for IL-6, IL-8, eotaxin, RANTES and sICAM-1 protein using ELISA. Maternal immune cell count and peripheral blood chemotactic response to plasma from pregnant and non-pregnant asthmatic subjects were also assessed. RESULTS: The presence of maternal asthma during pregnancy was associated with increased monocyte and neutrophil numbers, increased BEAS-2B cell production of IL-8 and sICAM-1 (P < 0.05) and increased chemotactic capacity relative to pregnant women without asthma. CONCLUSION: The results of this study suggest that circulating pregnancy-related factors enhance chemotactic mediators in epithelial cells in the presence of asthma. This may be one mechanism that contributes to pregnancy-induced changes in asthma.

Maternal and cord plasma cytokine and chemokine profile in pregnancies complicated by asthma.

The mechanisms contributing to worsening of asthma during pregnancy have not been well characterized. Both asthma and pregnancy are conditions associated with a skewing of the immune response from T helper (Th) 1 toward a Th2 response. We hypothesise that worsening of asthma during pregnancy may be due to an enhanced production of circulating proinflammatory cytokines and chemokines and this may be modified by the use of inhaled glucocorticoid treatment. Peripheral blood was collected from asthmatic (n=35) and control non-asthmatic patients (n=13) in the third trimester (30-37 weeks) of pregnancy. Fetal blood was collected from the umbilical vein of the placenta after delivery from normal (n=24) and pregnancies complicated by asthma (n=24). Plasma samples were assayed for IL-6, -8, eotaxin and RANTES using conventional ELISA. In addition, a range of Th1 and Th2 cytokines measured using Luminex system. There were no significant differences in the levels of maternal IL-6, IL-8, eotaxin and RANTES between asthmatics and nonasthmatics. The results of this study suggest that the presence of asthma does not result in an enhanced circulation of Th2 related cytokines and chemokines during the third trimester of pregnancy. Furthermore peripheral blood cytokine concentrations appear unaffected by inhaled glucocorticoid treatment. Cord plasma eotaxin concentrations were increased in pregnancies complicated by asthma, compared with control. This is the first study to show increased eotaxin production in the feto-placental unit of asthmatic pregnancies and may be one mechanism by which allergy susceptibility is increased in the offspring of asthmatic women.

Prenatal programming of the innate immune response following in utero exposure to inflammation: a sexually dimorphic process?

Maternal infection and inflammation are common events during pregnancy. This article documents evidence that suggests such inflammation compromises the development of the fetal innate immune response, in support of an in utero origins hypothesis of neonatal and childhood inflammatory disease. The potential for this response to exhibit sex specificity is also explored, based on evidence of sexually dimorphic placental responses to maternal inflammation.

Proteomics in asthma.

Proteomic approaches have already been successfully implemented in areas such as cancer research. Surprisingly, only a few proteomics analyses have been published reporting on the protein profiles associated with asthma. Although proteomics has its limitations and experimental challenges, it can successfully contribute to the understanding of a complex disease such as asthma. We have reviewed the current literature that has reported the use of proteomic techniques to identify proteins that may contribute to altered lung function in asthma. Only a few of these studies have used proteomic techniques on human tissues associated with asthma, while most research has been performed with animal models of asthma. Proteomic applications have been used as a complimentary technique to verify the suspected candidate proteins involved in asthma. In addition, novel proteins have been identified as potential therapeutic targets. Future collaboration between the different scientific disciplines using proteomic studies of animal models of asthma and confirmation of these findings in human tissues will significantly contribute to the understanding of the etiology of asthma and lead to the development of new therapeutic strategies for this highly prevalent disease.