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过分活跃的成纤维细胞通过ADAMTS4损害肺功能
2020-10-31 19:46

美国圣裘德儿童研究医院Paul G. Thomas研究组的最新研究发现,过分活跃的成纤维细胞通过ADAMTS4损害肺功能。2020年10月28日,《自然》在线发表了这项成果。

研究人员发现呼吸道病毒感染诱导了不同的成纤维细胞激活状态,研究人员将其称为细胞外基质(ECM)合成、损伤响应和干扰素响应状态。研究表明,在严重流感病毒感染期间,损伤反应性肺成纤维细胞的过度活性会导致致命性免疫病理变化。损伤敏感成纤维细胞通过产生ECM重塑酶(特别是ECM蛋白酶ADAMTS4)和炎性细胞因子来修饰肺微环境,从而促进免疫细胞浸润,但这同时会损害肺功能。

在三组人体实验中,下呼吸道中ADAMTS4的水平与季节性或禽流感病毒感染的严重程度有关。研发靶向损伤敏感肺成纤维细胞ECM蛋白酶活性的药物是保留患者严重呼吸道感染后肺功能和改善临床预后的潜在方法。

据了解,严重呼吸道感染可导致急性呼吸窘迫综合征(ARDS)。尚无有效药可改善ARDS患者的预后。尽管甲型/波多黎各/ 8/34流感病毒诱发的宿主炎症反应限制了病原体的传播并最终清除了病原体,但免疫病理是造成组织损伤和ARDS的主要因素。

附:英文原文

Title: Exuberant fibroblast activity compromises lung function via ADAMTS4

Author: David F. Boyd, E. Kaitlynn Allen, Adrienne G. Randolph, Xi-zhi J. Guo, Yunceng Weng, Catherine J. Sanders, Resha Bajracharya, Natalie K. Lee, Clifford S. Guy, Peter Vogel, Wenda Guan, Yimin Li, Xiaoqing Liu, Tanya Novak, Margaret M. Newhams, Thomas P. Fabrizio, Nicholas Wohlgemuth, Peter M. Mourani, Thomas N. Wight, Stacey Schultz-Cherry, Stephania A. Cormier, Kathryn Shaw-Saliba, Andrew Pekosz, Richard E. Rothman, Kuan-Fu Chen, Zifeng Yang, Richard J. Webby, Nanshan Zhong, Jeremy Chase Crawford, Paul G. Thomas

Issue&Volume: 2020-10-28

Abstract: Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although th influenza A/Puerto Rico/8/34 e host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

DOI: 10.1038/s41586-020-2877-5

Source:https://www.nature.com/articles/s41586-020-2877-5

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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