Developmental regulation of the lung in preparation for life after birth: hormonal and nutritional manipulation of local glucocorticoid action and uncoupling protein–2

Abstract

Glucocorticoid action has a major role in regulating fetal and postnatal lung development, although its impact on mitochondrial development is less well understood. Critically, the consequences of any change in glucocorticoid action and mitochondrial function in early life may not be limited to the postnatal period, but may extend into later life. This paper focuses on more recent findings on the impact of ontogeny, fetal cortisol status, maternal nutrient restriction and postnatal leptin administration on mitochondrial uncoupling protein (UCP)-2, glucocorticoid receptor (GR) and 11 -hydroxysteroid dehydrogenase type 1 (11 HSD1) isoform abundance in the lung. For example, in sheep, GR and 11 HSD1 mRNA are maximal at 140 days' gestation (term 147 days), while UCP2 mRNA peaks at 1 day after birth and then decreases with advancing age. In the fetus, chronic umbilical cord compression enhances the abundance of these genes, an outcome that can also be produced after birth following chronic, but not acute, leptin administration. Irrespective of the timing of maternal nutrient restriction in pregnancy, glucocorticoid sensitivity and UCP2 abundance are both upregulated in the lungs of the resulting offspring. In conclusion, prenatal and postnatal endocrine challenges have distinct effects on mitochondrial development in the lung resulting from changes in glucocorticoid action, which can persist into later life. As a consequence, changes in glucocorticoid sensitivity and mitochondrial protein abundance have the potential to be used to identify those at greatest risk of developing later lung disease.

Nutritional manipulation between early to mid-gestation: effects on uncoupling protein-2, glucocorticoid sensitivity, IGF-I receptor and cell proliferation but not apoptosis in the ovine placenta

“…This contrasts with adipose tissue in which nutritional programming of all of these proteins is observed (Mostyn et al 2003) and emphasizes their tissue-specific regulation (Gnanalingham et al 2005b(Gnanalingham et al , 2006. Unfortunately, we were unable to confirm whether UCP2 protein was similarly affected because of the current unavailability of specific antibodies for ovine UCP2 (Gnanalingham et al 2005f).…”

“…One aim of our study was, therefore, to determine whether glucocorticoid action within the placenta may be permanently reset following maternal NR. Glucocorticoids also have an important role in regulating uncoupling protein (UCP) abundance in the mitochondria of the fetus and newborn (Gnanalingham et al 2006) but the extent to which this may extend to the placenta is currently unknown.…”

Maternal weight, gestational weight gain and preschool wheezing: the Generation R Study

“…Higher BMI has been associated with higher leptin levels in pregnant females [13]. Leptin receptors are present in the fetal lung and may contribute to lung development in utero [28]. Also, leptin stimulates the production of pro-inflammatory cytokines, which might affect the development of the fetal immune system [13].…”

Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep

“…RNA integrity was further assessed by running on a denatured agarose/formaldehyde gel electrophoresis and 28S and 18S rRNA visualized in a 2:1 ratio. In order to maximize sensitivity, a two-tube approach to reverse transcription (RT) was adopted as previously described by Bispham et al (2005) and Gnanalingham et al (2005). The conditions used to generate first strand cDNA RTwere: 70 8C (5 min), 4 8C (5 min), 25 8C (5 min), 25 8C (10 min), 42 8C (1 h), 72 8C (10 min), and 4 8C (5 min).…”