It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40x8) that causes a transient change in lung function that resolves, rendering 40x8 adult animals functionally indistinguishable from room air controls. Here we reported that when infected with IAV, 40x8 mice display an early transient activation of TGFβ signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared to infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. While searching for potential activators of TGFβ signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40x8 mice compared to controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.

中文翻译：

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低剂量高氧为甲型流感感染后小鼠的纤维化启动气道

众所周知，用于治疗呼吸窘迫早产儿的补充氧气与永久性破坏肺部发育和宿主对甲型流感病毒 (IAV) 的反应有关。然而，许多肺部功能正常的婴儿在呼吸道病毒感染后也有高反应性的风险。我们最近报道了一种新的低剂量高氧小鼠模型（40% 持续 8 天；40x8），该模型会导致肺功能的短暂变化，从而使 40x8 成年动物在功能上与室内空气控制无法区分。在这里，我们报告说，当感染 IAV 时，与受感染的室内空气对照相比，40x8 小鼠显示出 TGFβ 信号传导的早期短暂激活和随后与支气管周围炎症（促纤维化巨噬细胞）和纤维化相关的气道高反应性，表明新生儿氧气诱导了隐藏的分子变化，这些变化为肺部过度反应性气道疾病做好了准备。在寻找 TGFβ 信号传导的潜在激活剂时，我们发现与对照组相比，幼稚 40x8 小鼠的血小板反应蛋白-1 (TSP-1) 升高，并在 IAV 感染之前和期间定位于肺巨核细胞和血小板。在患有支气管肺发育不良的早产儿的人体尸检样本中也发现了升高的 TSP-1。这些发现揭示了不会持久改变肺功能的低剂量氧气如何通过改变 TSP-1 等基因的表达来引发过度反应性气道疾病，从而有助于解释为什么肺功能正常的早产儿容易患上高反应性气道疾病。病毒感染后气道阻塞和发病率增加。