Wang Kimberley C W, Morton Jude S, Davidge Sandra T, Larcombe Alexander N, James Alan L, Donovan Graham M, Noble Peter B
Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, Alberta, Canada.
Respirology. 2017 Oct;22(7):1329-1335. doi: 10.1111/resp.13071. Epub 2017 May 17.
Intrauterine growth restriction (IUGR) is associated with asthma development. We hypothesized that IUGR disrupts airway development leading to postnatal structural abnormalities of the airway that predispose to disease. This study therefore examined structural changes to the airway and lung in a rat model of maternal hypoxia-induced IUGR.
Pregnant rats were housed under hypoxic conditions (11.5% O ) from gestational days (GDs) 13 to 20 (pseudoglandular-canalicular stages, i.e. period of airway development) and then returned to normoxic conditions (21% O ). A control group of pregnant rats was housed under normoxic conditions throughout pregnancy. Weights of male offspring were recorded at birth and 7 weeks of age (adulthood), at which point lungs were fixed for morphometry and stereology (n = 6/group), or bronchoalveolar lavage fluid (BALF) was collected for cell counts (n = 6/group).
IUGR offspring were lighter at birth compared with control, but not at 7 weeks. While there was no difference in mean airway dimensions or lung volume, there was greater anatomical variation in airway lumen area in the IUGR group. A mathematical model of the human lung was used to show that greater heterogeneity in lumen area in IUGR-affected individuals increases bronchoconstriction during simulated bronchial challenge. More macrophages were identified in the BALF of IUGR offspring.
The rat model demonstrates that IUGR leads to a more heterogeneous distribution of airway lumen calibre in adulthood with potential implications for bronchoconstriction in human subjects. Together with increased lung macrophages, these findings support a phenotypic shift after IUGR that may impact disease susceptibility.
宫内生长受限（IUGR）与哮喘的发生有关。我们推测，IUGR会干扰气道发育，导致出生后气道结构异常，从而易患疾病。因此，本研究在母体缺氧诱导的IUGR大鼠模型中，研究了气道和肺的结构变化。
妊娠大鼠在妊娠第13至20天（假腺泡-小管期，即气道发育时期）置于低氧环境（11.5%氧气）中，然后恢复到常氧环境（21%氧气）。一组妊娠大鼠在整个孕期置于常氧环境作为对照。记录雄性后代出生时和7周龄（成年）时的体重，此时将肺固定用于形态学和体视学分析（每组n = 6），或收集支气管肺泡灌洗液（BALF）进行细胞计数（每组n = 6）。
与对照组相比，IUGR后代出生时体重较轻，但7周龄时体重无差异。虽然平均气道尺寸和肺体积没有差异，但IUGR组气道腔面积的解剖学变异更大。使用人类肺的数学模型表明，IUGR个体中腔面积的更大异质性会增加模拟支气管激发试验期间的支气管收缩。在IUGR后代的BALF中发现了更多的巨噬细胞。
大鼠模型表明，IUGR会导致成年期气道腔内径分布更加不均匀，这可能对人类受试者的支气管收缩产生影响。连同肺巨噬细胞增加，这些发现支持IUGR后可能影响疾病易感性的表型转变。
