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 ARDS 1 , 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. Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.

中文翻译：

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旺盛的成纤维细胞活性通过 ADAMTS4 损害肺功能

严重的呼吸道感染可导致急性呼吸窘迫综合征 (ARDS) 1 。没有有效的药物疗法已被证明可以改善 ARDS 患者的预后。虽然 th 流感 A/波多黎各/8/34 e 宿主炎症反应限制传播并最终清除病原体，免疫病理学是组织损伤和 ARDS 1, 2 的主要因素。在这里我们证明呼吸道病毒感染诱导不同的成纤维细胞激活状态，我们称之为细胞外基质 (ECM) 合成、损伤反应和干扰素反应状态。我们提供的证据表明，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动会导致致命的免疫病理学。通过产生 ECM 重塑酶 - 特别是 ECM 蛋白酶 ADAMTS4 - 和炎症细胞因子，损伤反应性成纤维细胞改变肺微环境，以牺牲肺功能为代价促进强大的免疫细胞浸润。在三个人类参与者队列中，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。针对损伤反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前途的方法来保护肺功能和改善严重呼吸道感染后的临床结果。呼吸系统的病毒感染诱导旺盛的成纤维细胞活性，导致细胞外基质的广泛重塑和细胞因子的释放，