Pulmonary fibrosis (PF) is a fatal fibrotic lung disease without any options to halt disease progression. Feasible evidence suggests that aberrant metabolism of amino acids may play a role in the pathoetiology of PF. However, the exact impact of kynurenine (Kyn), a metabolite derived from tryptophan (Trp) on PF is yet to be addressed. This study aims to elucidate the role of kynurenine in both the onset and advancement of PF. Liquid chromatography–tandem mass spectrometry was employed to assess Kyn levels in patients with idiopathic PF and PF associated with Sjögren’s syndrome. Additionally, a mouse model of PF induced by bleomycin was utilized to study the impact of Kyn administration. Furthermore, cell models treated with TGF-β1 were used to explore the mechanism by which Kyn inhibits fibroblast functions. We demonstrated that high levels of Kyn are a clinical feature in both idiopathic PF patients and primary Sjögren syndrome associated PF patients. Further studies illustrated that Kyn served as a braking molecule to suppress fibroblast functionality, thereby protecting mice from bleomycin-induced lung fibrosis. The protective effects depend on AHR, in which Kyn induces AHR nuclear translocation, where it upregulates PTEN expression to blunt TGF-β mediated AKT/mTOR signaling in fibroblasts. However, in fibrotic microenviroment, the expression of AHR is repressed by methyl-CpG-binding domain 2 (MBD2), a reader interpreting the effect of DNA methylation, which results in a significantly reduced sensitivity of Kyn to fibroblasts. Therefore, exogenous administration of Kyn substantially reversed established PF. Our studies not only highlighted a critical role of Trp metabolism in PF pathogenesis, but also provided compelling evidence suggesting that Kyn could serve as a promising metabolite against PF.

中文翻译：

---

犬尿氨酸作为信号分子，通过增强 AHR-PTEN 轴来减轻肺纤维化


肺纤维化（PF）是一种致命的纤维化肺部疾病，没有任何方法可以阻止疾病进展。可行的证据表明，氨基酸代谢异常可能在 PF 的病理学中发挥作用。然而，犬尿氨酸 (Kyn)（一种源自色氨酸 (Trp) 的代谢物）对 PF 的确切影响尚待解决。本研究旨在阐明犬尿氨酸在 PF 发生和进展中的作用。采用液相色谱-串联质谱法评估特发性 PF 和干燥综合征相关 PF 患者的 Kyn 水平。此外，利用博莱霉素诱导的 PF 小鼠模型来研究 Kyn 给药的影响。此外，使用TGF-β1处理的细胞模型来探索Kyn抑制成纤维细胞功能的机制。我们证明，高水平的 Kyn 是特发性 PF 患者和原发性干燥综合征相关 PF 患者的临床特征。进一步的研究表明，Kyn 作为抑制成纤维细胞功能的制动分子，从而保护小鼠免受博莱霉素诱导的肺纤维化。保护作用取决于 AHR，其中 Kyn 诱导 AHR 核易位，上调 PTEN 表达，从而减弱成纤维细胞中 TGF-β 介导的 AKT/mTOR 信号传导。然而，在纤维化微环境中，AHR 的表达受到甲基 CpG 结合域 2 (MBD2) 的抑制，MBD2 是解释 DNA 甲基化效应的解读器，导致 Kyn 对成纤维细胞的敏感性显着降低。因此，外源性给予 Kyn 可以显着逆转已建立的 PF。 我们的研究不仅强调了色氨酸代谢在 PF 发病机制中的关键作用，而且提供了令人信服的证据，表明 Kyn 可以作为一种有前途的 PF 代谢物。