Highlights of a Satellite Symposium at the 47th Annual Meeting of the European Society for Paediatric Research
A new approach to acceleration of fetal lung
maturation by pioglitazone
Florian GuthmannDepartment of Neonatology, Charite-CCM, Berlin, Germany
Induction of lung maturity via the use of antenatal glucocorticoids has been shown to improve the respiratoryoutcomes of preterm infants. A large body of evidence over the 20-year period from 1972 to 1995 in over 3300infants with RDS reported favourable outcomes following treatment with corticosteroids. The number needed totreat to induce lung maturation before 31 weeks of gestation was calculated to be 4. Around the year 2000 therewere increased concerns regarding corticosteroid treatment in pregnant women. Animal studies have shown thatnormal and repeat doses of corticosteroids: • inhibit fetal growth• increase fetal blood pressure• may decrease birthweight. Corticosteroids may also have harmful effects on neuronal myelination, the development of lung morphology andendocrinological development. Given these concerns the focus has turned towards an alternative to glucorticoid treatment and the potential for alternative agents that may be administered instead of, or in combination with, glucocorticoids.
PPAR agonists: an alternative to glucocorticoids?
PPARs are group of nuclear receptor isoforms (alpha, gamma and delta) that regulate several biological functions.
In particular, the activation of PPAR gamma by an agonist, such as those commonly used in the treatment of type2 diabetes, results in:• reduced insulin resistance• modified adipocyte differentiation• inhibited VEGF-induced angiogenesis• reduced leptin levels leading to an increased appetite • anti-inflammatory effects – evidenced by a fall in certain IL (i.e. IL-6).
It has been hypothesised that LCFA are bound to fatty acids by two types of FABP: hard (H) and epidermal (E). E- and H-FABP transport LCFA within the cytosol and modulate phospholipid synthesis. Double knockout micehave been used to study the expression of caveolin-1 and of PPAR-gamma and its cofactor. Caveolin-1 expressionwas significantly increased in this model, and caveolin ions may disassociate from the membrane and transportLCFA to the intracellular membrane or the nucleus. The pharmacological effect of the PPAR-gamma agonist pioglitazone has been demonstrated in H- and E-FABPdouble knockout mice. In these knockout mice decreased FA uptake, reduced beta-oxidation and reducedincorporation of palmitic acid into diacylglycerol, triglycerides and DPPC were observed; administration of pioglitazone restored the uptake of FA, increased beta-oxidation and the de novo
synthesis of phosphorylated choline. Apart from these activities, PPAR gamma agonists may exert their potential therapeutic role in the management ofBPD in preterm babies interfering with the expression of the ABCA3, a causative gene for fatal surfactantdeficiency. This gene has been shown to be up-regulated by glucocorticoids in lung alveolar type II cells.Therefore, the beneficial effect that glucocorticoids exhibit in lung maturation and prevention of BPD might bemediated via this pathway.
In a similar study, Guthmann et al. administered pioglitazone to pregnant rats starting on fetal day 14.5 andanimals were sacrificed on day 19.5 (unpublished data). In the fetal lung of non-treated rats there was very littleABCA3 expression; however, following pioglitazone administration there was greater ABCA3 expression. At day19.5 there was also a significant increase in the expression of surfactant proteins A, B, and C in the fetal lung ofrats receiving antenatal pioglitazone (Figure 1)
Neonatal Pulmonary Symposium
Antenatal administration ofpioglitazone resulted in a 5-fold
Figure 1. Expression of surfactant protein in fetal rat lung following 5days of administration of pioglitazone.
increase in the incorporation ofdiacylgycerol and phosphatidyl
incorporation of choline intophosphatidyl choline was alsoslightly increased in A549 humancell line following 24-hour
administration of ciglitazone. A positive control performed withdexamethasone produced similar
After administration of pioglitazone,there was increased expression of
gamma and ABCA3 in rat lungtissues. There was also an increasein surfactant-associated proteins A,B, and C. Interestingly, there was no PPAR response element in surfactant-associated protein genes. It has beenpostulated that surfactant proteins may be induced by PPAR independently as evidenced in other pathways orthere may be an indirect effect via ABCA3 which increases transport into the lamellar body and a feedbackmechanism increases the expression of surfactant proteins. Ciglitazone has been shown to increase theincorporation of choline into phosphatidyl choline in A549 cell lines.
The beneficial effects of the PPAR-gamma agonists observed in animal studies and in human cell lines indicatethat this class of agents may potentially offer an alternative to glucocorticoids in the treatment of preterm infants with BPD.
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2. Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respiratory distress
syndrome: discussion. Am J Obstet Gynecol 1995; 173: 335-344.
3. Aghajafari F, Murphy K, Matthews S, et al. Repeated doses of antenatal corticosteroids in animals. A systemic review. Am J Obstet
4. Guthmann F, Hohoff C, Fechner H, et al. Expression of fatty-acid-binding proteins in cells involved in lung-specific lipid metabolism.
5. Yoshida I, Ban N, Inagaki N. Expression of ABCA3, a causative gene for fatal surfactant deficiency, is up-regulated by glucocorticoid
in lung alveolar type II cells. Biochem Biophys Res Comm 2004; 323: 547-555.
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