美国加州大学Dean Sheppard团队近日取得一项新成果。经过不懈努力，他们发现肺泡成纤维细胞系调控肺部炎症和纤维化。这一研究成果发表在2024年7月10日出版的国际学术期刊《自然》上。

研究人员发现肺特化肺泡成纤维细胞具有多种分子状态，在促进肺纤维化损伤反应中发挥不同功能。研究人员建立了一种独特的靶向肺泡成纤维细胞的遗传工具，以证明它们在平衡状态下为肺泡干细胞提供生态位，并表明这种生态位的丧失会导致对急性肺损伤的过度反应。系谱示踪表明肺泡成纤维细胞是多种新生成纤维细胞亚群的主要来源，这些亚群在损伤后依次受到炎症和促纤维化信号的诱导。

研究人员在人肺纤维化中发现了相似但不完全相同的成纤维细胞系。TGFβ负调节损伤后早期出现的炎性成纤维细胞亚群，并刺激其分化为纤维化的成纤维细胞，从而引发肺泡内纤维化。阻断肺泡成纤维细胞系中的纤维化成纤维细胞可减轻肺部纤维化，但会加剧肺部炎症。这些结果表明，肺泡成纤维细胞系在维持肺泡正常稳态，和调控对肺损伤连续反应方面发挥着多方面的功能。

据介绍，成纤维细胞遍布全身，具有维持组织稳态的功能。最近的研究发现了健康和损伤组织中的多种成纤维细胞亚群，但损伤诱导的成纤维细胞系的起源和功能仍不清楚。

附：英文原文

Title: Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis

Author: Tsukui, Tatsuya, Wolters, Paul J., Sheppard, Dean

Issue&Volume: 2024-07-10

Abstract: Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues1,2, but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFβ negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury.

DOI: 10.1038/s41586-024-07660-1

Source: https://www.nature.com/articles/s41586-024-07660-1