Epithelial Stress and Apoptosis Underlie Hermansky-Pudlak Syndrome-associated Interstitial Pneumonia
Epithelial Stress and Apoptosis Underlie Hermansky-Pudlak Syndrome-associated Interstitial Pneumonia
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DOI：
10.1164/rccm.200909-1414oc
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发表时间：
2010-07-01
影响因子：
24.7
通讯作者：
Guenther, Andreas
中科院分区：
文献类型：
--
作者：
Mahavadi, Poornima;Korfei, Martina;Guenther, Andreas
理由。Hermansky-Pudlak综合征相关性间质性肺炎（HPSIP）的分子机制尚不清楚，但与特发性肺纤维化一样，可能与慢性肺泡上皮II型细胞（AECII）损伤有关。在3月龄和9月龄时处死HPS 1、HPS 2和HPS 6单突变小鼠，以及HPS 1/2和HPS 1/6双突变和遗传背景小鼠。在用hemalaun伊红染色的肺切片中进行定量形态测定。肺纤维化程度通过三色染色和羟脯氨酸测定来评估。通过电喷雾电离质谱法分析表面活性剂脂质。表面活性蛋白，细胞凋亡，溶酶体和内质网应激标志物进行了研究，Western印迹和免疫组化。细胞增殖测定水溶性tetrazolium盐-1和bromodeoxyuridine assays.Measurements和主要结果：自发性和缓慢进行性HPSIP观察HPS 1/2双突变体，但不是在其他HPS突变体，胸膜下发病3个月，在9个月的全面纤维化。在这些小鼠中，广泛的表面活性剂异常AECII中遇到的早期溶酶体应激（组织蛋白酶D诱导），晚期内质网应激（激活转录因子-4（ATF 4），C/EBP同源蛋白（CHOP）诱导），和显着的细胞凋亡。这些发现在人类HPSIP中得到了充分证实。此外，组织蛋白酶D过表达导致MLE-12细胞的凋亡和NIH 3 T3成纤维细胞的增殖增加与转染cells.Conclusions的条件培养基孵育：广泛受损的表面活性物质的运输和分泌的基础上溶酶体和内质网应激与凋亡的AECII在HPSIP，从而导致HPSIP的发展。
Rationale. The molecular mechanisms underlying Hermansky-Pudlak syndrome associated interstitial pneumonia (HPSIP) are poorly understood but, as in idiopathic pulmonary fibrosis, may be linked to chronic alveolar epithelial type II cell (AECII) injury.Objectives: We studied the development of fibrosis and the role of AECII injury in various murine models of HPS.Methods: HPS1, HPS2, and HPS6 monomutant mice, and HPS1/2 and HPS1/6 double-mutant and genetic background mice, were killed at 3 and 9 months of age. Quantitative morphometry was undertaken in lung sections stained with hemalaun eosin. The extent of lung fibrosis was assessed by trichrome staining and hydroxyproline measurement. Surfactant lipids were analyzed by electrospray ionization mass spectrometry. Surfactant proteins, apoptosis, and lysosomal and endoplasmic reticulum stress markers were studied by Western blotting and immunohistochemistry. Cell proliferation was measured by water-soluble tetrazolium salt-1 and bromodeoxyuridine assays.Measurements and Main Results: Spontaneous and slowly progressive HPSIP was observed in HPS1/2 double mutants, but not in other HPS mutants, with subpleural onset at 3 months and full-blown fibrosis at 9 months. In these mice, extensive surfactant abnormalities were encountered in AECII and were paralleled by early lysosomal stress (cathepsin D induction), late endoplasmic reticulum stress (activating transcription factor-4 [ATF4], C/EBP homologous protein [CHOP] induction), and marked apoptosis. These findings were fully corroborated in human HPSIP. In addition, cathepsin D overexpression resulted in apoptosis of MLE-12 cells and increased proliferation of NIH 3T3 fibroblasts incubated with conditioned medium of the transfected cells.Conclusions: Extensively impaired surfactant trafficking and secretion underlie lysosomal and endoplasmic reticulum stress with apoptosis of AECII in HPSIP, thereby causing the development of HPSIP.