Crystal Deposits in Macrophages and Distal Lung Remodeling: A Tale of Aging in SFTPC-Deficient Mice.
Crystal Deposits in Macrophages and Distal Lung Remodeling: A Tale of Aging in SFTPC-Deficient Mice.
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巨噬细胞中的晶体沉积和远端肺重塑：SFTPC 缺陷小鼠的衰老故事。
DOI：
10.1165/rcmb.2020-0018ed
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发表时间：
2020
影响因子：
6.4
通讯作者：
Karmouty-Quintana,Harry
中科院分区：
文献类型：
--
作者：
Weng,Tingting;Karmouty-Quintana,Harry
间质性肺病（ILD）最常见的表现之一是特发性肺纤维化（IPF），这是一种慢性、进行性和致死性疾病。在过去10年中，美国IPF的患病率增加了两倍，影响了约180，000名美国人（1）。IPF发病机制的核心是肺泡II型细胞损伤，伴随间充质细胞活化和免疫细胞失调，导致细胞外基质沉积增强和肺重塑（2）。与IPF相关的重要风险因素包括吸烟史和高龄（1）。表面活性剂基因SFTPC和SFTPA的突变与成人和儿童ILD相关，其中常见机制包括内质网（ER）应激、蛋白质聚集和由于产生SFTPC突变形式导致的细胞凋亡（3）。这可能是最好的例证，优雅的研究中，小鼠携带突变形式的SFTPC发展自发性肺纤维化（4）。与SFTPC突变形式同样重要的是与家族性ILD相关的SFTPC缺失（5）。在这方面，已经报道了博来霉素诱导的肺损伤后SFTPC（和其他表面活性蛋白）的损失（6）。此外，还报告了SFTPCJ/J小鼠中的炎症反应（7）和纤维化反应（8）加剧。然而，SFTPC缺乏对肺损伤的慢性影响尚未完全了解。466-478）将SFTPC消耗与衰老联系起来，并证明尽管存在早期发育缺陷，包括体重增加较慢、肺体积减少、炎性细胞浸润和肺功能缺陷，但小鼠能够在30至40周龄时进行补偿（9）。无论这种恢复如何，例如改善的肺功能参数和减少的炎性细胞浸润，肺损伤的组织病理学特征是普遍的，一些早在10周龄时。肺结构的这些改变包括在50至60周龄之间检测到的纤维化损伤证据之前出现的空域扩大。这些观察结果具有重要意义，因为它们表明，尽管SFTPC J/J小鼠中存在早期肺功能缺陷，但这些动物能够适应并表现出正常的肺功能（与年龄匹配的SFTPC+小鼠相比）。尽管肺功能值正常，但在50 - 60周龄之间，纤维化肺损伤的证据在组织学上变得明显，与氧饱和度百分比降低相关。尽管有这些令人信服的观察结果，但作者错过了纵向跟踪衰老标志物的机会，如b-半乳糖苷酶或g-H2 AX，这可能有助于进一步了解小鼠衰老与SFTPC缺乏症之间的联系。
One of the most widespread presentations of interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and fatal disease. The prevalence of IPF in the United States has increased twofold in the last 10 years, affecting approximately 180,000 Americans (1). Central to the pathogenesis of IPF is injury to alveolar type II cells, concomitant with mesenchymal cell activation and immune cell dysregulation resulting in enhanced extracellular matrix deposition and lung remodeling (2). Important risk factors associated with IPF include a history of smoking and advanced age (1). Mutations of surfactant genes, SFTPC and SFTPA, have been linked with adult and childhood ILD, where common mechanisms include endoplasmic reticulum (ER) stress, protein aggregation, and apoptosis as a result of production of mutant forms of SFTPC (3). This may be best exemplified by elegant studies where mice carrying a mutant form of SFTPC developed spontaneous lung fibrosis (4). Equally as important as mutant forms of SFTPC is the loss of SFTPC that has been associated with familial ILD (5). In this regard, loss of SFTPC (and other surfactant proteins) after bleomycin-induced lung injury (6) has been reported. In addition, exacerbated inflammatory (7) and fibrotic responses (8) in SFTPCJ/J mice have also been reported. However, the chronic effects of SFTPC deficiency on lung injury are not fully understood.In this issue of the Journal, Ruwisch and colleagues (pp. 466–478) link SFTPC depletion with aging and demonstrate that despite early developmental defects, including slower body weight gain, reduced lung volume, inflammatory cell infiltration, and deficits in lung function, mice are able to compensate by 30 to 40 weeks of age (9). Regardless of this recovery, exemplified by improved lung function parameters and reduced inflammatory cell infiltration, histopathological features of lung injury are prevalent, some as early as 10 weeks of age. These alterations in pulmonary architecture include airspace enlargement that appears to precede evidence of fibrotic injury that is detected between 50 and 60 weeks of age. These observations are significant, because they demonstrate that despite early deficits in lung function in SFTPC J/J mice, these animals are able to adapt and present with normal lung function (compared with age-matched SFTPC+ mice). Although normal lung function values were present, evidence of fibrotic lung injury became apparent histologically between 50 and 60 weeks of age that correlated with reductions in percent oxygen saturation. Despite these compelling observations, the authors missed an opportunity to longitudinally track markers of senescence, such as b-galactosidase or g-H2AX, that may help to further understand the link between aging and SFTPC deficiency in mice.
影响因子：
4
作者：
C. Richardson;I. Lehman
通讯作者：
I. Lehman