Targeted Injury of Type II Alveolar Epithelial Cells Induces Pulmonary Fibrosis
Targeted Injury of Type II Alveolar Epithelial Cells Induces Pulmonary Fibrosis
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DOI：
10.1164/rccm.200810-1615oc
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发表时间：
2010-02-01
影响因子：
24.7
通讯作者：
Simon, Richard H.
中科院分区：
文献类型：
--
作者：
Sisson, Thomas H.;Mendez, Michael;Simon, Richard H.
原理：受损肺泡上皮的无效修复被认为是导致肺纤维化的原因。为了支持这一理论，在患有特发性肺纤维化的人的肺和纤维化肺病的动物模型中发现了上皮细胞异常，包括增生、凋亡和肺泡基底膜的持续剥脱。此外，影响再生能力或导致11型肺泡上皮细胞损伤/凋亡的基因突变已在家族性肺纤维化中被鉴定。虽然这些研究结果是令人信服的，有没有研究表明，肺泡上皮细胞或，更具体地说，11型细胞在瘢痕形成process.Objectives的直接作用：要确定是否有针对性的损伤11型细胞将导致肺fibrosis.Methods：一个转基因小鼠产生表达人白喉毒素受体11型肺泡上皮细胞。将白喉毒素给予这些动物，以特异性靶向11型上皮损伤。肺纤维化进行了评估，组织学和羟脯氨酸measurement. Measures和主要结果：白喉毒素治疗的转基因小鼠开发了大约两倍的增加，他们的肺羟脯氨酸含量在第21和28天白喉毒素治疗后。纤维化与11型细胞损伤一起发展。组织学评价显示，弥漫性胶原蛋白沉积与斑片状地区更融合的疤痕和相关的alveolar contraction.Conclusions：在我们的模型中，11型细胞损伤的设置肺纤维化的发展提供了证据，为特发性肺纤维化中看到的上皮缺陷和相应的疤痕面积之间的因果关系。
Rationale: Ineffective repair of a damaged alveolar epithelium has been postulated to cause pulmonary fibrosis. In support of this theory, epithelial cell abnormalities, including hyperplasia, apoptosis, and persistent denudation of the alveolar basement membrane, are found in the lungs of humans with idiopathic pulmonary fibrosis and in animal models of fibrotic lung disease. Furthermore, mutations in genes that affect regenerative capacity or that cause injury/apoptosis of type 11 alveolar epithelial cells have been identified in familial forms of pulmonary fibrosis. Although these findings are compelling, there are no studies that demonstrate a direct role for the alveolar epithelium or, more specifically, type 11 cells in the scarring process.Objectives: To determine if a targeted injury to type 11 cells would result in pulmonary fibrosis.Methods: A transgenic mouse was generated to express the human diphtheria toxin receptor on type 11 alveolar epithelial cells. Diphtheria toxin was administered to these animals to specifically target the type 11 epithelium for injury. Lung fibrosis was assessed by histology and hydroxyproline measurement.Measurements and Main Results: Transgenic mice treated with diphtheria toxin developed an approximately twofold increase in their lung hydroxyproline content on Days 21 and 28 after diphtheria toxin treatment. The fibrosis developed in conjunction with type 11 cell injury. Histological evaluation revealed diffuse Collagen deposition with patchy areas of more confluent scarring and associated alveolar contraction.Conclusions: The development of lung fibrosis in the setting of type 11 cell injury in our model provides evidence for a causal link between the epithelial defects seen in idiopathic pulmonary fibrosis and the corresponding areas of scarring.