Hirakawa Hiroshi, Pierce Richard A, Bingol-Karakoc Gulbin, Karaaslan Cagatay, Weng Meiqian, Shi Guo-Ping, Saad Ali, Weber Ekkehard, Mariani Thomas J, Starcher Barry, Shapiro Steve D, Cataltepe Sule
Division of Newborn Medicine, Brigham and Women's Hospital, Thorn 1019, 75 Francis Street, Boston, MA 02115, USA.
Am J Respir Crit Care Med. 2007 Oct 15;176(8):778-85. doi: 10.1164/rccm.200704-519OC. Epub 2007 Aug 2.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease that adversely affects long-term pulmonary function as well as neurodevelopmental outcomes of preterm infants. Elastolytic proteases have been implicated in the pathogenesis of BPD. Cathepsin S (cat S) is a cysteine protease with potent elastolytic activity. Increased levels and activity of cat S have been detected in a baboon model of BPD.
To investigate whether deficiency of cat S alters the course of hyperoxia-induced neonatal lung injury in mice.
Newborn wild-type and cat S-deficient mice were exposed to 80% oxygen for 14 days. Histologic and morphometric analysis were performed and bronchoalveolar lavage protein and cells were analyzed. Lung elastin was assessed by real-time polymerase chain reaction, in situ hybridization, desmosine analysis, and Hart's stain. Distribution of myofibroblasts was analyzed by immunofluorescence. Hydroxyproline content of lung tissues was measured.
Hyperoxia-exposed cat S-deficient mice were protected from growth restriction and had improved alveolarization, decreased septal wall thickness, lower number of macrophages, and lower protein concentration in bronchoalveolar lavage fluid. alpha-Smooth muscle actin-expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hyperoxia-exposed mouse lungs and were significantly less in cat S-deficient lungs. Lung hydroxyproline content was increased in hyperoxia-exposed wild-type, but not in cat S-deficient lungs. Desmosine content was significantly reduced in both genotypes with hyperoxia.
Cathepsin S deficiency improves alveolarization, and attenuates macrophage influx and fibroproliferative changes in hyperoxia-induced neonatal mouse lung injury.
支气管肺发育不良（BPD）是一种慢性肺部疾病，会对早产儿的长期肺功能以及神经发育结局产生不利影响。弹性蛋白酶已被认为与BPD的发病机制有关。组织蛋白酶S（cat S）是一种具有强大弹性蛋白溶解活性的半胱氨酸蛋白酶。在BPD的狒狒模型中已检测到cat S的水平和活性增加。
研究cat S缺乏是否会改变小鼠高氧诱导的新生儿肺损伤进程。
将新生野生型和cat S缺陷型小鼠暴露于80%氧气中14天。进行组织学和形态计量学分析，并分析支气管肺泡灌洗蛋白和细胞。通过实时聚合酶链反应、原位杂交、锁链素分析和哈特染色评估肺弹性蛋白。通过免疫荧光分析肌成纤维细胞的分布。测量肺组织的羟脯氨酸含量。
暴露于高氧的cat S缺陷型小鼠免受生长限制，肺泡化改善，间隔壁厚度减小，巨噬细胞数量减少，支气管肺泡灌洗液中的蛋白浓度降低。表达α-平滑肌肌动蛋白的肌成纤维细胞至少部分解释了暴露于高氧的小鼠肺中间质细胞增多的现象，并且在cat S缺陷型肺中明显减少。暴露于高氧的野生型肺中羟脯氨酸含量增加，但cat S缺陷型肺中未增加。两种基因型在高氧环境下锁链素含量均显著降低。
组织蛋白酶S缺乏可改善肺泡化，并减轻高氧诱导的新生儿小鼠肺损伤中的巨噬细胞流入和纤维增生性变化。
