Department of Medicine, Div. of Pulmonary Medicine, Johns Hopkins University, Baltimore, MD, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L266-73. doi: 10.1152/ajplung.00239.2010. Epub 2010 Dec 3.
Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O(2) profile in patients with OSA. We exposed adult C57BL/6J mice to 3 mo of IH with a fraction of inspired oxygen (F(I)(O(2))) nadir of 5% 60 times/h during the 12-h light phase. Control mice were exposed to room air. Lung volumes were measured by quasistatic pressure-volume (PV) curves under anesthesia and by water displacement postmortem. Lungs were processed for morphometry, and the mean airspace chord length (Lm) and alveolar surface area were determined. Lung tissue was stained for markers of proliferation (proliferating cell nuclear antigen), apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling), and type II alveolar epithelial cells (surfactant protein C). Gene microarrays were performed, and results were validated by real-time PCR. IH increased lung volumes by both PV curves (air vs. IH, 1.16 vs. 1.44 ml, P < 0.0001) and water displacement (P < 0.01) without changes in Lm, suggesting that IH increased the alveolar surface area. IH induced a 60% increase in cellular proliferation, but the number of proliferating type II alveolocytes tripled. There was no increase in apoptosis. IH upregulated pathways of cellular movement and cellular growth and development, including key developmental genes vascular endothelial growth factor A and platelet-derived growth factor B. We conclude that IH increases alveolar surface area by stimulating lung growth in adult mice.
阻塞性睡眠呼吸暂停（OSA）会增加心血管发病率和死亡率，这归因于间歇性低氧（IH）。IH 对肺结构和功能的影响尚不清楚。我们使用了一种慢性 IH 的小鼠模型，该模型模拟了 OSA 患者的 O2 谱。我们让成年 C57BL/6J 小鼠在 12 小时光照期内，每小时接受 60 次、持续 3 个月、吸入氧分数（F(I)(O(2)))最低值为 5%的 IH。对照小鼠则暴露于室内空气中。在麻醉下通过准静态压力-容量（PV）曲线和死后通过水置换来测量肺容量。对肺组织进行形态计量学处理，并确定平均空气空间弦长（Lm）和肺泡表面积。用增殖（增殖细胞核抗原）、凋亡（末端脱氧核苷酸转移酶 dUTP 缺口末端标记）和 II 型肺泡上皮细胞（表面活性蛋白 C）的标志物对肺组织进行染色。进行基因微阵列分析，并通过实时 PCR 验证结果。IH 通过 PV 曲线（空气与 IH，1.16 与 1.44ml，P<0.0001）和水置换（P<0.01）增加了肺容量，而 Lm 没有变化，这表明 IH 增加了肺泡表面积。IH 诱导了 60%的细胞增殖增加，但增殖的 II 型肺泡细胞数量增加了两倍。凋亡没有增加。IH 上调了细胞运动和细胞生长发育的途径，包括血管内皮生长因子 A 和血小板衍生生长因子 B 等关键发育基因。我们的结论是，IH 通过刺激成年小鼠的肺生长来增加肺泡表面积。
