過分活躍的成纖維細胞通過ADAMTS4損害肺功能
作者：
小柯機器人發布時間：2020/10/31 19:46:27
美國聖裘德兒童研究醫院Paul G. Thomas研究組的最新研究發現，過分活躍的成纖維細胞通過ADAMTS4損害肺功能。2020年10月28日，《自然》在線發表了這項成果。
研究人員發現呼吸道病毒感染誘導了不同的成纖維細胞激活狀態，研究人員將其稱為細胞外基質（ECM）合成、損傷響應和幹擾素響應狀態。研究表明，在嚴重流感病毒感染期間，損傷反應性肺成纖維細胞的過度活性會導致致命性免疫病理變化。損傷敏感成纖維細胞通過產生ECM重塑酶（特別是ECM蛋白酶ADAMTS4）和炎性細胞因子來修飾肺微環境，從而促進免疫細胞浸潤，但這同時會損害肺功能。
在三組人體實驗中，下呼吸道中ADAMTS4的水平與季節性或禽流感病毒感染的嚴重程度有關。研發靶向損傷敏感肺成纖維細胞ECM蛋白酶活性的藥物是保留患者嚴重呼吸道感染後肺功能和改善臨床預後的潛在方法。
據了解，嚴重呼吸道感染可導致急性呼吸窘迫症候群（ARDS）。尚無有效藥可改善ARDS患者的預後。儘管甲型/波多黎各/ 8/34流感病毒誘發的宿主炎症反應限制了病原體的傳播並最終清除了病原體，但免疫病理是造成組織損傷和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