Widowski Helene, Ophelders Daan R M G, van Leeuwen Anaïs J C N, Nikkels Peter G J, Severens-Rijvers Carmen A H, LaPointe Vanessa L S, Cleutjens Jack P M, Hütten Matthias C, Kemp Matthew W, Payne Matthew S, Saito Masatoshi, Usuda Haruo, Newnham John P, Jobe Alan H, Kramer Boris W, Delhaas Tammo, Wolfs Tim G A M, Reynaert Niki L
Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of BioMedical Engineering, Maastricht University Medical Center, Maastricht, The Netherlands.
Pediatr Res. 2021 Sep;90(3):549-558. doi: 10.1038/s41390-020-01204-9. Epub 2020 Oct 18.
Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools.
In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied.
Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs.
Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes.
In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally. This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.
绒毛膜羊膜炎是胎盘和胎膜的宫内感染，是早产儿发生包括支气管肺发育不良（BPD）在内的不良肺部结局的常见危险因素，BPD的特征是肺泡发育停滞。由于内源性上皮干细胞/祖细胞对器官发生和组织修复至关重要，我们研究了宫内炎症是否会对这些重要的祖细胞池产生负面影响。
在绵羊绒毛膜羊膜炎模型中，在妊娠125天早产前2天或7天（急性炎症）将胎儿羊膜腔内暴露于脂多糖（LPS），或羊膜腔内暴露于微小脲原体42天（慢性炎症）。研究肺功能、肺内源性上皮干细胞/祖细胞池及下游功能标志物。
7天LPS组和42天脲原体组肺功能得到改善。然而，宫内炎症导致近端气道中P63⁺基底细胞减少，远端气道中SOX-9表达降低和TTF-1⁺Club细胞减少。Ⅱ型细胞数量减少与增殖降低及Ⅰ型细胞标志物水通道蛋白5（Aqp5）表达降低有关，提示祖细胞功能受损。慢性脲原体感染仅影响远端气道，而急性炎症影响整个肺部的干细胞/祖细胞群体。
急性和慢性产前炎症改善了肺功能，但以干细胞/祖细胞改变为代价，这可能会破坏正常的肺发育，从而易导致不良的产后结局。
在本研究中，产前炎症改善了肺功能，但以干细胞/祖细胞改变为代价，这可能会破坏正常的肺发育，从而易导致不良的产后结局。重要的是，我们证明这些重要改变在出生前就已开始。到目前为止，干细胞/祖细胞功能障碍仅在出生后被证实。本研究表明，针对围产期炎症应激对未成熟肺的影响的临床方案应尽早启动，理想情况下应在子宫内启动。在此背景下，我们的数据表明，促进肺内源性干细胞功能或修复的干预措施具有很大前景。
