PDF(Pubmed)
Abstract：
BACKGROUND: Interstitial lung diseases (ILDs) are a diverse group of conditions characterized by inflammation and fibrosis in the lung. In some patients with ILD, a progressive fibrotic phenotype develops, which is associated with an irreversible decline in lung function and a poor prognosis.
METHODS: The pathological mechanisms that underlie this process culminate in fibroblast activation, proliferation, and differentiation into myofibroblasts, which deposit extracellular matrix proteins and result in fibrosis. Upstream of fibroblast activation, epithelial cell injury and immune activation are known initiators of fibrosis progression, with multiple diverse cell types involved. Recent years have seen an increase in our understanding of the complex and interrelated processes that drive fibrosis progression in ILD, in part due to the advent of single-cell RNA sequencing technology and integrative multiomics analyses. Novel pathological mechanisms have been identified, which represent new targets for drugs currently in clinical development. These include phosphodiesterase 4 inhibitors and other molecules that act on intracellular cyclic adenosine monophosphate signaling, as well as inhibitors of the autotaxin-lysophosphatidic acid axis and α v integrins. Here, we review current knowledge and recent developments regarding the pathological mechanisms that underlie progressive fibrotic ILD, including potential therapeutic targets.
CONCLUSIONS: Knowledge of the pathological mechanisms that drive progressive fibrosis in patients with ILD has expanded, with the role of alveolar endothelial cells, the immune system, and fibroblasts better elucidated. Drugs that target novel mechanisms hold promise for expanding the future therapeutic armamentarium for progressive fibrotic ILD.
METHODS: The pathological mechanisms that underlie this process culminate in fibroblast activation, proliferation, and differentiation into myofibroblasts, which deposit extracellular matrix proteins and result in fibrosis. Upstream of fibroblast activation, epithelial cell injury and immune activation are known initiators of fibrosis progression, with multiple diverse cell types involved. Recent years have seen an increase in our understanding of the complex and interrelated processes that drive fibrosis progression in ILD, in part due to the advent of single-cell RNA sequencing technology and integrative multiomics analyses. Novel pathological mechanisms have been identified, which represent new targets for drugs currently in clinical development. These include phosphodiesterase 4 inhibitors and other molecules that act on intracellular cyclic adenosine monophosphate signaling, as well as inhibitors of the autotaxin-lysophosphatidic acid axis and α v integrins. Here, we review current knowledge and recent developments regarding the pathological mechanisms that underlie progressive fibrotic ILD, including potential therapeutic targets.
CONCLUSIONS: Knowledge of the pathological mechanisms that drive progressive fibrosis in patients with ILD has expanded, with the role of alveolar endothelial cells, the immune system, and fibroblasts better elucidated. Drugs that target novel mechanisms hold promise for expanding the future therapeutic armamentarium for progressive fibrotic ILD.
摘要：
背景：间质性肺病（ILD）是一组以肺部炎症和纤维化为特征的疾病。在一些ILD患者中，进行性纤维化表型发展，这与不可逆的肺功能下降和不良预后有关。
方法：这一过程的病理机制最终导致成纤维细胞活化，扩散,分化为肌成纤维细胞，沉积细胞外基质蛋白并导致纤维化。成纤维细胞活化的上游，上皮细胞损伤和免疫激活是已知的纤维化进展的启动，涉及多种不同的细胞类型。近年来，我们对驱动ILD纤维化进展的复杂和相关过程的理解有所增加，部分原因是单细胞RNA测序技术和综合多组学分析的出现。已经确定了新的病理机制，这代表了目前正在临床开发的药物的新靶点。这些包括磷酸二酯酶4抑制剂和其他作用于细胞内环磷酸腺苷信号传导的分子，以及自分泌运动因子-溶血磷脂酸轴和αv整合素的抑制剂。这里,我们回顾了有关进行性纤维化ILD的病理机制的最新知识和最新进展，包括潜在的治疗靶点。
结论：对导致ILD患者进行性纤维化的病理机制的了解有所扩大，与肺泡内皮细胞的作用，免疫系统,和成纤维细胞更好地阐明。靶向新机制的药物有望扩大进行性纤维化ILD的未来治疗性医疗设备。
方法：这一过程的病理机制最终导致成纤维细胞活化，扩散,分化为肌成纤维细胞，沉积细胞外基质蛋白并导致纤维化。成纤维细胞活化的上游，上皮细胞损伤和免疫激活是已知的纤维化进展的启动，涉及多种不同的细胞类型。近年来，我们对驱动ILD纤维化进展的复杂和相关过程的理解有所增加，部分原因是单细胞RNA测序技术和综合多组学分析的出现。已经确定了新的病理机制，这代表了目前正在临床开发的药物的新靶点。这些包括磷酸二酯酶4抑制剂和其他作用于细胞内环磷酸腺苷信号传导的分子，以及自分泌运动因子-溶血磷脂酸轴和αv整合素的抑制剂。这里,我们回顾了有关进行性纤维化ILD的病理机制的最新知识和最新进展，包括潜在的治疗靶点。
结论：对导致ILD患者进行性纤维化的病理机制的了解有所扩大，与肺泡内皮细胞的作用，免疫系统,和成纤维细胞更好地阐明。靶向新机制的药物有望扩大进行性纤维化ILD的未来治疗性医疗设备。
