Resetting proteostasis in aged animals with ISRIB prevents recruitment of profibrotic monocyte-derived alveolar macrophages during pulmonary fibrosis [dataset 2]

Aging is among the most important risk factors for the development of pulmonary fibrosis. Inappropriate or prolonged activation of the integrated stress response has been implicated in the pathobiology of both aging and pulmonary fibrosis. We found that a small molecule that relieves translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity pulmonary fibrosis in young and old mice. We demonstrate that severe fibrosis in old mice was associated with increased number of pathogenic monocyte-derived alveolar macrophages. Using transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased recruitment of pathogenic monocyte-derived alveolar macrophages. Thus our data suggest that inhibition of the integrated stress response in the lung epithelium can ameliorate pulmonary fibrosis by preventing the recruitment of monocyte-derived alveolar macrophages.

衰老乃是肺纤维化发生发展最为关键的危险因素之一。整合应激反应（integrated stress response, ISR）的异常激活或持续活化，与衰老及肺纤维化的病理生物学过程密切相关。我们发现，一种可缓解整合应激反应激活诱导的翻译抑制的小分子化合物ISRIB，能够减轻年轻与老年小鼠的肺纤维化严重程度。研究证实，老年小鼠的重度肺纤维化与致病性单核细胞源性肺泡巨噬细胞数量增加存在显著关联。通过转录组分析（transcriptomic profiling），我们发现ISRIB可调控肺泡上皮细胞中的应激信号通路，从而减少致病性单核细胞源性肺泡巨噬细胞的招募。综上，本研究数据表明，抑制肺上皮细胞的整合应激反应，可通过阻断单核细胞源性肺泡巨噬细胞的招募来改善肺纤维化。