Department of Physiology, University of Toronto, Toronto, ON, Canada.
Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
J Dev Orig Health Dis. 2021 Dec;12(6):963-974. doi: 10.1017/S204017442000135X. Epub 2021 Jan 7.
Respiratory distress syndrome results from inadequate functional pulmonary surfactant and is a significant cause of mortality in preterm infants. Surfactant is essential for regulating alveolar interfacial surface tension, and its synthesis by Type II alveolar epithelial cells is stimulated by leptin produced by pulmonary lipofibroblasts upon activation by peroxisome proliferator-activated receptor γ (PPARγ). As it is unknown whether PPARγ stimulation or direct leptin administration can stimulate surfactant synthesis before birth, we examined the effect of continuous fetal administration of either the PPARγ agonist, rosiglitazone (RGZ; Study 1) or leptin (Study 2) on surfactant protein maturation in the late gestation fetal sheep lung. We measured mRNA expression of genes involved in surfactant maturation and showed that RGZ treatment reduced mRNA expression of LPCAT1 (surfactant phospholipid synthesis) and LAMP3 (marker for lamellar bodies), but did not alter mRNA expression of PPARγ, surfactant proteins (SFTP-A, -B, -C, and -D), PCYT1A (surfactant phospholipid synthesis), ABCA3 (phospholipid transportation), or the PPARγ target genes SPHK-1 and PAI-1. Leptin infusion significantly increased the expression of PPARγ and IGF2 and decreased the expression of SFTP-B. However, mRNA expression of the majority of genes involved in surfactant synthesis was not affected. These results suggest a potential decreased capacity for surfactant phospholipid and protein production in the fetal lung after RGZ and leptin administration, respectively. Therefore, targeting PPARγ may not be a feasible mechanistic approach to promote lung maturation.
呼吸窘迫综合征是由于功能性肺表面活性物质不足引起的，是早产儿死亡的重要原因。表面活性物质对于调节肺泡界面表面张力至关重要，其由 II 型肺泡上皮细胞合成，并受肺脂肪成纤维细胞产生的瘦素刺激，而瘦素的产生则受到过氧化物酶体增殖物激活受体 γ（PPARγ）的激活。由于尚不清楚 PPARγ 刺激或直接给予瘦素是否能在出生前刺激表面活性物质的合成，我们研究了连续给予胎儿 PPARγ 激动剂罗格列酮（RGZ；研究 1）或瘦素（研究 2）对胎羊晚期肺表面活性物质蛋白成熟的影响。我们测量了参与表面活性物质成熟的基因的 mRNA 表达情况，并表明 RGZ 处理降低了 LPCAT1（表面活性物质磷脂合成）和 LAMP3（板层小体标志物）的 mRNA 表达，但不改变 PPARγ、表面活性蛋白（SFTP-A、-B、-C 和 -D）、PCYT1A（表面活性物质磷脂合成）、ABCA3（磷脂转运）或 PPARγ 靶基因 SPHK-1 和 PAI-1 的 mRNA 表达。瘦素输注显著增加了 PPARγ 和 IGF2 的表达，并降低了 SFTP-B 的表达。然而，大多数参与表面活性物质合成的基因的 mRNA 表达并未受到影响。这些结果表明，在给予 RGZ 和瘦素后，胎儿肺中的表面活性物质磷脂和蛋白质产生能力可能分别降低。因此，靶向 PPARγ 可能不是促进肺成熟的可行机制方法。
