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[Another new discovery about fibrosis. Stephen]
<http://www.sciencedaily.com/releases/2010/12/101220150936.htm>
New Study Upends Thinking About How Liver Disease Develops
ScienceDaily (Dec. 28, 2010) — In the latest of a series of related papers,
researchers at the University of California, San Diego School of Medicine, with
colleagues in Austria and elsewhere, present a new and more definitive
explanation of how fibrotic cells form, multiply and eventually destroy the
human liver, resulting in cirrhosis. In doing so, the findings upend the
standing of a long-presumed marker for multiple fibrotic diseases and reveal the
existence of a previously unknown kind of inflammatory white blood cell.The
results are published in the early online edition of the Proceedings of the
National Academy of Sciences.In all types of chronic diseases, healthy,
functioning tissues are progressively replaced by fibrous scarring, which
renders the tissues or larger organ increasingly dysfunctional until,
eventually, it fails. The process is called fibrosis. In the human liver, the
end result is cirrhosis, the 12th leading cause of death by disease in the
United States with roughly 27,000 deaths annually. Fibrosis occurs in other organs as well, such as the heart, kidneys and lungs, with comparable deadly effect.Scientists do not fully understand the process of fibrosis, particularly how problematic fibroblast cells are created. For years, conventional wisdom has posited that fibroblasts are likely to be transformed epithelial cells, a conversion called "epithelial to mesenchymal transition" or EMT. A protein called fibroblast-specific protein 1 (FSP1) has long been considered to be a reliable indicator of fibroblasts in injured organs undergoing tissue remodeling and has been broadly used to identify the presence of fibrotic disease.The new research undermines the validity of prevailing assumptions about EMT and FSP1, but also opens the door to new avenues of investigation that could ultimately lead to improved detection and treatment of cirrhosis and similar conditions."This work, along with earlier papers, puts into question a whole area of research -- at least in terms of the liver" said David Brenner, MD, Vice Chancellor for Health Sciences, dean of the UC San Diego School of Medicine and co-author of the paper. "The old evidence and assumptions about the source of fibroblasts and the role of FSP1 as a marker are not valid."Specifically, in experiments using cell cultures, human liver samples and mouse models, the researchers found no evidence of EMT -- that transformed epithelial cells became liver fibroblasts. Rather, endogenous stellate cells appear to be the culprit, though the scientists note many types of cells seem to contribute, directly or indirectly, to liver fibrosis.Likewise, experiments proved FSP1 to be an unreliable marker for fibrosis. Cells containing FSP1 increased in human and experimental liver disease and in liver cancer, but researchers found that liver fibroblasts do not express the protein, nor do hepatic stellate cells -- a major cell type involved in liver fibrosis. Similarly, FSP1 was determined not to be a marker for myofibroblasts (a fibroblast with some properties of a smooth muscle cell) or any precursors of myofibroblasts."There have been hundreds of papers based on FSP1 as a marker," said Brenner. "That thinking now seems to have been a mistake. One of the take-home messages of this paper is that FSP1 clearly can't be reliably used as a marker."On the other hand, the scientists discovered that FSP1 is a consistent marker for a previously unknown subset of inflammatory white blood cells or macrophages found in injured livers. The protein appears to also perform biological functions in the macrophages, though these remain to be determined."It's a whole new class of monocytes," said Brenner. "We don't know what they do, but they're worth investigating."Co-authors of the study are Christoph H. Osterreicher of the Department of Medicine, Laboratory of Gene Regulation and Signal Transduction and Department of Pharmacology, all at UC San Diego, and of the Institute of Pharmacology, Center for Physiology and Pharmacology and the Department of Internal Medicine, Division of Gastroenterology at Medical University of Vienna in Austria; Melitta Penz-Osterreicher of the Department of Medicine at UC San Diego and the Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna; Sergei I. Grivennikov and Monica Guma of the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, UC San Diego; Ekaterina K. Koltsova of the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology; Christian Datz of the Department of Internal Medicine, General Hospital Oberndorf in Austria; Roman Sasik and Gary Hardiman of Biomedical Genomics Microarray Facility, Department of Medicine, UC San Diego; and Michael Karin of the Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology at UC San Diego.Email or share this story:| More
--------------------------------------------------------------------------------
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff)
from materials provided by University of California - San Diego, via EurekAlert!, a service of AAAS.
--------------------------------------------------------------------------------
Journal Reference:
1.Christoph H. Österreicher, Melitta Penz-Österreicher, Sergei I. Grivennikov,
Monica Guma, Ekaterina K. Koltsova, Christian Datz, Roman Sasik, Gary Hardiman,
Michael Karin, and David A. Brenner. Fibroblast-specific protein 1 identifies an
inflammatory subpopulation of macrophages in the liver. Proceedings of the
National Academy of Sciences, 2010; DOI: 10.1073/pnas.1017547108
<http://www.sciencedaily.com/rele ... 20150936.htm>
新的研究Upends思考如何开发肝病
科学日报（12月28，2010） - 在一个系列中最新的相关论文，
研究人员在美国加州大学圣地亚哥分校医学院和
在奥地利和其他地方的同事们，现在一个新的和更明确的
肝纤维化细胞如何形成，繁衍和解释最终破坏
人体肝脏，导致肝硬化。这样做，结果竖直的
站在一个多纤维化疾病长期推定标记，揭示了
存在的炎性白细胞cell.The一种以前未知
结果发表在早期的诉讼程序的网络版
国家科学院的慢性疾病，健康的所有类型的Sciences.In，
运作组织正逐步取代纤维疤痕，这
呈现较大的组织或器官功能失调，直到越来越多，
最终，它失败。这个过程被称为纤维化。在人类的肝脏，
最终的结果是肝硬化，第12届受到疾病的主要原因中的死亡
美国每年有大约27,000人死亡。纤维化发生在其他机关以及，如心脏，肾脏和肺，具有可比性的致命effect.Scientists并不完全了解纤维化进程，特别是成纤维细胞是如何创建的问题。多年来，传统的智慧已经假定，成纤维细胞很可能是上皮细胞转化，转换被称为“上皮向间质转化”或EMT的。一个叫做成纤维蛋白特异性蛋白1（FSP1）一直被认为是在受伤的器官组织重塑成纤维细胞进行可靠的指标，并已广泛用于确定新的研究纤维化disease.The存在破坏了当时的假设的有效性。约EMT和FSP1，但也开启了大门，新途径的调查最终可能导致肝硬化和完善的检测和类似疾病的治疗“随着这项工作较早的文件，放到整个问题的研究领域 - 在在肝脏方面至少“戴维说Brenner医师表示，健康科学副校长，院长，加州大学圣地亚哥分校医学院和合作的论文的作者。 “。老证据和成纤维细胞的来源及FSP1作为标记的作用假设是无效的”具体在实验中，采用细胞培养，人肝样品和小鼠模型，研究人员没有发现EMT的证据 - 即转化上皮细胞成为肝细胞。相反，内生星状细胞似乎是罪魁祸首，虽然科学家们注意到许多类型的细胞似乎贡献，直接或间接向肝fibrosis.Likewise，实验证明FSP1纤维化是一种不可靠的指标。细胞含FSP1增加对人力和实验性肝疾病和肝癌，但研究人员发现，肝细胞不表达的蛋白质，也没有肝星状细胞 - 细胞类型中的主要参与肝纤维化。同样，FSP1决心不成为肌纤维母细胞标记（与平滑肌细胞的成纤维细胞的一些性质）或肌纤维母细胞的前体。“有作为的一个标志FSP1数以百计的论文，说：”布伦纳。 “这种想法现在看来已经是一个错误。本文件的拿回家的消息之一是，FSP1显然不能可靠地作为一个标记。”另一方面，科学家发现，FSP1是一致的标记对于炎症的白血细胞或巨噬细胞集发现以前未知的肝脏中受伤。该蛋白似乎也履行了巨噬细胞生物学功能，虽然这些仍有待确定。“这是一个全新的单核细胞新类，说：”布伦纳。 “我们不知道他们做什么，但它们的价值进行调查。”合作研究的作者是克里斯托夫阁下Osterreicher的医学系，实验室，基因调控和信号转导药理学教研室，所有在加州圣地亚哥，和药理学，生理学和药理学研究中心和内科，胃肠病科研究所在奥地利维也纳医科大学;丽达Penz - Osterreicher的医学系在加州大学圣地亚哥分校和部内科三，胃肠病学和肝病，维也纳医科大学司;谢尔盖一Grivennikov和莫妮卡的基因调控和信号转导，古玛药理教研室实验室，加州大学圣地亚哥分校;叶卡捷琳娜的K.炎症的生物学部Koltsova ，拉霍亚变态反应与免疫学研究所，基督教Datz的内科，在奥地利总医院道夫处，罗马Sasik基因芯片技术和生物医学基金加里哈迪曼，医学系，加州大学圣地亚哥分校，以及实验室的迈克尔卡林基因调控和信号转导，在加州大学药理学系Diego.Email或分享这个故事：|更多
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故事来源：
上面的故事转载（每日科学人员与编辑修改）
由加州大学提供的材料 - 圣地亚哥，通过稿，一个美国科学促进会的服务。
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引文：
1.Christoph阁下Österreicher，丽达Penz - Österreicher，谢尔盖一Grivennikov，
莫妮卡古马，叶卡捷琳娜光Koltsova，基督教Datz，罗马Sasik，加里哈迪曼，
迈克尔卡琳和大卫答：布伦纳。成纤维细胞特异性蛋白1列出一
炎性细胞亚群在肝巨噬细胞。诉讼的
国家科学院院士，2010;分类号：10.1073/pnas.1017547108 |
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发表于 2010-12-24 17:11
