Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues^1,2, 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.

成纤维细胞遍布全身，具有维持组织稳态的功能。最近的研究已经确定了健康和受伤组织中不同的成纤维细胞亚群^1,2 ，但损伤诱导的成纤维细胞谱系的起源和功能作用仍不清楚。在这里，我们发现肺特化的肺泡成纤维细胞呈现多种分子状态，在促进对纤维化肺损伤的反应中发挥不同的作用。我们开发了一种专门针对肺泡成纤维细胞的遗传工具，以证明其在为肺泡干细胞稳态提供生态位方面的作用，并表明该生态位的丧失会导致对急性肺损伤的过度反应。谱系追踪将肺泡成纤维细胞确定为损伤后由炎症和促纤维化信号依次驱动的多个新生成纤维细胞亚群的主要起源。我们在人肺纤维化中发现了相似但不完全相同的成纤维细胞谱系。 TGFβ 负向调节损伤后早期出现的炎症成纤维细胞亚群，并刺激分化为纤维化成纤维细胞，从而引发肺泡内纤维化。阻断肺泡成纤维细胞谱系中纤维化成纤维细胞的诱导可以消除纤维化，但会加剧肺部炎症。这些结果证明了肺泡成纤维细胞谱系在维持正常肺泡稳态和协调对肺损伤的连续反应中的多方面作用。