Exuberant fibroblast activity compromises lung function via ADAMTS4.
Exuberant fibroblast activity compromises lung function via ADAMTS4.
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DOI：
10.1038/s41586-020-2877-5
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发表时间：
2020-11
期刊：
影响因子：
64.8
通讯作者：
Thomas PG
中科院分区：
文献类型：
--
作者：
Boyd DF;Allen EK;Randolph AG;Guo XJ;Weng Y;Sanders CJ;Bajracharya R;Lee NK;Guy CS;Vogel P;Guan W;Li Y;Liu X;Novak T;Newhams MM;Fabrizio TP;Wohlgemuth N;Mourani PM;PALISI Pediatric Intensive Care Influenza (PICFLU) Investigators;Wight TN;Schultz-Cherry S;Cormier SA;Shaw-Saliba K;Pekosz A;Rothman RE;Chen KF;Yang Z;Webby RJ;Zhong N;Crawford JC;Thomas PG
严重的呼吸道感染可导致急性呼吸窘迫综合征（ARDS）。没有有效的药物治疗已被证明可以改善ARDS患者的结局。虽然宿主的炎症反应限制了病原体的扩散并最终清除病原体，但免疫病理学是组织损伤和ARDS的主要原因。在这项研究中，我们证明，呼吸道病毒感染诱导不同的成纤维细胞活化状态，我们称之为细胞外基质（ECM）合成，损伤反应，干扰素反应。我们提供的证据表明，在严重的流感病毒感染期间，损伤反应性肺成纤维细胞的旺盛活性驱动了致命的免疫病理学。通过产生ECM重塑酶（特别是ECM蛋白酶ADAMTS-4）和炎性细胞因子，损伤响应性成纤维细胞改变肺微环境以促进稳健的免疫细胞浸润，但以肺功能为代价。在三个人类队列中，下呼吸道中ADAMTS-4的水平与季节性和禽流感病毒感染的严重程度相关。靶向损伤响应性肺成纤维细胞的ECM蛋白酶活性的治疗剂可以提供一种有希望的方法来保护肺功能并改善严重呼吸道感染后的临床结果。
Severe respiratory infections can result in acute respiratory distress syndrome (ARDS). There are no effective pharmacological therapeutics that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS. In this study, we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive, and interferon-responsive. We provide evidence that the exuberant activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM remodeling enzymes, in particular the ECM protease ADAMTS-4, and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three human cohorts, the levels of ADAMTS-4 in the lower respiratory tract were associated with the severity of seasonal and avian influenza virus infections. A therapeutic 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.
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影响因子：
8.8
作者：
Hall MW;Geyer SM;Guo CY;Panoskaltsis-Mortari A;Jouvet P;Ferdinands J;Shay DK;Nateri J;Greathouse K;Sullivan R;Tran T;Keisling S;Randolph AG;Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators
通讯作者：
Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network PICFlu Study Investigators
DOI：
10.1038/nri3665
发表时间：
2014-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
81.5
作者：
Matthay, Michael A.;Zemans, Rachel L.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
影响因子：
20.3
作者：
Hope, Chelsea;Foulcer, Simon;Asimakopoulos, Fotis
通讯作者：
Asimakopoulos, Fotis
影响因子：
12.3
作者：
Kelwick R;Desanlis I;Wheeler GN;Edwards DR
通讯作者：
Edwards DR